Lymphoma-associated Hemophagocytic Lymphohistiocytosis Research Articles

Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): a scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome driven by pathologic activation of cytotoxic T-lymphocytes and macrophages. Despite advances in diagnostics and management, adult patients with lymphoma-associated HLH (LA-HLH) harbor particularly poor prognosis and optimal treatment remains challenging. As systematic data on LA-HLH are scarce, we aimed to synthesize research evidence by thorough analysis of the published literature in PubMed (MEDLINE-database) within the context of a scoping review. Of 595 search results, 132 articles providing information on 542 patients were reviewed and analyzed. Median patient age was 60 years (range, 18-98) with male predominance (62.7%). B- and T-NHL were equally represented (45.6% and 45.2%), Hodgkin's lymphoma was reported in 8.9% of the cases. The majority of patients (91.6%) presented in Ann-Arbor-Stages III and IV, and bone marrow infiltration was observed in a significant proportion of patients (61.5%). Soluble CD25 levels were markedly elevated (median 10,000 U/ml), with levels beyond 10,000 U/ml indicating unfavorable prognosis for 30-day and overall survival. 66.8% of the patients died after median 5.1 months. LA-HLH remains a clinical challenge requiring specialized management. Timely diagnosis and appropriate lymphoma-specific treatment are of utmost importance to enhance patient outcomes.

Clinical Significance of Serum High-Density Lipoprotein Cholesterol and Its Dynamic Change in Patients with Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

Background: The lipid profile in serum is frequently dysregulated in lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). We aimed to explore the clinical significance of serum lipoprotein cholesterol in lymphoma-associated HLH. Methods: Patients with lymphoma-associated HLH were included. Serum levels of baseline low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) were collected. Serum levels of LDL-c and HDL-c after treatment (first test after treatment, time interval ≥ 14 days) were also collected. Results: A total of 169 lymphoma-associated HLH were included. T/NK-cell lymphomas (n=88, 52.1%) account for over half of cases. Low HDL-c (< 1.03 mmol/L) was observed in 161 (95.3%) patients and low LDL-c (< 2.6 mmol/L) was presented in 145 (85.8%) patients. The best cutoff of 0.50 mmol/L for HDL-c was determined to predict the 60-day survival. Patients with HDL-c ≥ 0.50 mmol/L showed a significantly higher 60-day survival rate than patients with HDL-c <0.50 mmol/L (70.9% vs 42.2%, p < 0.001.). Patients with HDL-c ≥ 0.50 mmol/L also showed longer overall survival (OS) (median OS: 346 days vs 34 days, p < 0.001). LDL-c showed no significant impacts on 60-day survival and OS. Dynamic data of HDL-c were available in 69.2% (117) of the patients. The median interval between the two tests was 18 (IQR: 15-25) days. The level of HDL-c after treatment increased in 80.3% (94/117) of the patients. The ratio of post-treatment HDL-c/baseline HDL-c was calculated and the median number was 1.67 (IQR: 1.05-2.48). The ratio was significantly lower in the patients with T/NK-cell malignancies than those with B-cell lymphomas (median 1.40 versus 1.97, p < 0.001). A ratio of 0.78 was determined as the best cutoff to predict the 60-day survival. Patients with a ratio<0.78 had significantly reduced 60-day survival (42.4% vs 76.6%, P=0.0035, Figure 1A) and OS (median 36 days vs 407 days, P=0.0001, Figure 1B). Then we divided these patients with available data into two groups based on baseline HDL-c and the ratio of post-treatment HDL-c/baseline HDL-c: Group 1 included patients with baseline HDL-c ≥ 0.5 mmol/L and Ratio ≥ 0.78, while others were classified as Group 2. Patients in Group 2 had significantly reduced 60-day survival (57.5% vs 87.6%, P=0.0003, Figure 1C) and OS (median 107 days vs not reached, P=0.0001, Figure 1D) than Group 1. Conclusion: Our study demonstrated serum HDL-c and its dynamic Change were robust and clinically feasible markers for predicting the outcomes of patients with lymphoma-associated HLH.

Efficacy and Safety of CD19-Specific CAR-T Cell Therapy Following Immunochemotherapy in Newly Diagnosed B-Cell Lymphoma Associated Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) represents a grave and potentially fatal systemic inflammatory condition. Lymphoma associated hemophagocytic lymphohistiocytosis (LAHS), as a common type in secondary HLH, suffers the worst outcome among sHLH. B cell Lymphoma associated hemophagocytic lymphohistiocytosis (B-LAHS) typically presents as high-risk lymphoma and is associated with a poorer prognosis compared to B cell lymphoma without HLH with standard first-line chemoimmunotherapy. As a result, there is an urgent need for more effective therapeutic strategies. Recent advancements in chimeric antigen receptor (CAR) T-cell therapy have demonstrated remarkable responses in relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL), as well as in some high-risk newly diagnosed B-cell lymphoma. However, There have been no clinical reports regarding the application of CAR-T cell treatment as part of first-line therapy in B-LAHS. We assessed the effectiveness and safety of autologous anti-CD19 CAR-T cell therapy following an immunochemotherapeutic regimen based on R-DEP (Rituximab-doxorubicin-etoposide-methylprednisolone) as a first-line treatment option for patients with B-LAHS. As of 1 July 2023, a cohort of 13 patients diagnosed with B-LAHS（with 3 cases enrolled before registration for clinical trials）was recruited for evaluation and met the criteria for assessing treatment efficacy at our institution. The overall response rate (ORR) for HLH was 100% (with 7 cases achieving complete response and 6 cases achieving partial response) prior to infuse CAR-T cells and the ORR for lymphoma also was 100% (with 10 cases achieving complete response and 3 cases achieving partial response) on the time of a month after CAR-T cell infusion. As of the follow-up date on 1 July 2023 (with a median follow-up time of 14 months), all 13 patients were still alive, 12 cases maintained sustained remission, while 1 case experienced relapse at 16 months after CAR-T cell infusion. The median overall survival (OS) has not been reached, and the median progression-free survival (PFS) was 31.5 months. To provide comparison, we included a group of 26 patients diagnosed with B-LAHS who did not receive CAR-T cell therapy during the same period. The non-CAR-T group demonstrated a significantly lower median OS of 5.93 months and a median PFS of 4.43 months, highlighting the superior prognosis of the CAR-T group (p < 0.001). Regarding adverse events, the CAR-T group exhibited a cytokine release syndrome (CRS) incidence of 53.8% (7/13) and an immune effector cell-associated neurotoxicity syndrome (ICANS) incidence of 30.7% (4 /13), all of which were classified as grade 1. None of the patients experienced non-hematologic toxicity of grade ≥3. While all 13 patients developed cytopenias, hematologic toxicity reactions ≥ grade 3 were observed in 76.9% (10 /13) of patients, but blood cell counts recovered within 3 weeks. Robust expansion of CAR T-cells occurred in all patients, with a median time to peak expansion of 8 days. Importantly, no exacerbation of hemophagocytic syndrome occurred following CAR-T cell infusion, and no patients succumbed to adverse events. In conclusion, our findings suggest that CD19 CAR-T cell treatment exhibits high efficacy as part of first-line therapy for B-LAHS, with a manageable safety profile.

The Lymphocyte Subsets Activation Profiles in Peripheral Blood May Contribute to the Diagnosis of Natural Killer/T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

The lymphocyte subsets activation profiles in peripheral blood may contribute to the diagnosis of natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis Background: Hemophagocytic lymphohistiocytosis (HLH) is a rampant and potentially fatal systemic hyperinflammation characterized by dysfunction of macrophages and cytotoxic T cells. Natural killer/T-cell lymphoma (NKTCL) has been reported to be one of the most common etiologies of HLH among hematologic neoplasms. Although, the diagnosis of natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) refers to the HLH-2004 diagnostic guidelines for primary HLH, most of them are based on non-specific clinical features. Identification of the immunophenotype characteristics is important for the diagnosis of NK/T-LAHS. In this study, we investigated the lymphocyte subsets activation profiles of peripheral blood mononuclear cells (PBMC) from NKTCL patients, and preliminarily screened molecular marker with potential diagnostic value for NK/T-LAHS. Methods: This study retrospectively collected peripheral blood samples from 58 patients diagnosed with NKTCL in Sun Yat-sen University Cancer Center from September 2020 to December 2022. Among them, 29 patients had HLH at the time of enrollment, and peripheral blood samples from 10 healthy people were collected as the control group. NKTCL was diagnosed according to the 2016 WHO classification of malignant lymphoma. All HLH patients met HLH-2004 diagnostic criteria and primary HLH was excluded. Flow cytometric staining of PBMC was performed on BD Fortessa according to the manufacturer's instructions. All samples were analyzed by Flowjo（V10）software. The ROC curve was drawn according to the percentage of lymphocyte subsets to determine the optimal cutoff threshold. RStudio 4.2.1 was used to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratio (LR) of the related indicators. Graphpad prism 8.0.1 and SPSS 26.0 (IBM) was used for drawing and statistical analysis. All statistical tests were two-sided, and p＜0.05 were considered statistically significant. Results:The median age of 58 patients was 41 (range, 18-83) years old, and 10 patients (17.2%) had poor performance status (ECOG PS≥2). Forty-two patients (72.4%) were stage III-IV, and 26 patients (44.8%) had PINK-E score≥3. Firstly, we compared the immune cell activation profiles between healthy donors, NKTCL patients with or without HLH. We observed that the proportion of functionally activated T cells, NK cells, NKT cells that expressed CD86, CD69, or HLADR was significantly higher than healthy donors ( p＜0.05), except for CD86+NK cell levels was no significance between the three groups (Figure1). In addition, the percentage of CD86+NK/T cells, CD69+NK cells, HLADR+NK cells and HLADR+NKT cells were significantly higher than NKTCL patients without HLH and healthy controls( p＜0.05), and no significant difference of these immune cells subsets between those non-HLH patients and healthy controls was observed (Figure1). Based on the significance of these lymphocyte subsets in NKTCL patients with and without HLH, we evaluated the diagnostic value of CD86+NKT cells, CD69+NK cells, HLADR+NK cells, and HLADR+NKT cells in NK/T-LAHS patients by ROC analysis to determine the optimal diagnostic threshold. We observed that HLADR+NK > 15.9% could better distinguish NK/T-LAHS from non-HLH patients, with a sensitivity of 0.759 (95%CI: 0.603-0.914) and specificity of 0.828(95%CI:0.690-0.965), and the AUC was 0.775 (95%CI:0.647-0.904) (Table 1). HLADR+NK cells may have potential application value for the diagnosis of NK/T-LAHS. Conclusions: These activated T cells, NK cells, and NKT cells that express functional activation markers was increased in NK/T-LAHS patients. Among them, HLADR+NK > 15.9% could better distinguish NK/T-LAHS from NKTCL patients without HLH and healthy donors, which may be a potential biomarker for the diagnosis of NK/T-LAHS patients and contribute to better management.

The Clinical Significance and Prognostic Value of Serum Beta-2 Microglobulin in Adult Lymphoma-Associated Hemophagocytic Lymphohistiocytosis: A Multicenter Analysis of 326 Patients

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by an excessive immune response. Beta-2 microglobulin (B2M) forms the light chain section of the major histocompatibility complex (MHC) class Ⅰ antigen. The prognostic role of B2M in lymphoma-associated HLH remains to be determined. This study was to investigate the prognostic role of serum B2M in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). Methods: The clinical and laboratory characteristics of adult patients in a multicenter cohort with lymphoma-associated HLH who had baseline serum B2M levels between August 2009 and June 2023 were retrospectively analyzed. The diagnosis of HLH was established according to the HLH-2004 criteria. Results: A total of 326 cases were included and the median serum B2M level was 5.19 mg/L. The most common subtype of lymphoma was T/NK cell lymphoma (51.8%, 169/326), followed by B-cell non-Hodgkin lymphoma (45.4%, 148/227) and Hodgkin lymphoma 8/326 (2.5). The optimal cut-off value of serum B2M for predicting overall survival was 8.73 mg/L (p < 0.0001). Patients were divided into two subgroups by the optimal cut-off value. The median survival was 21 days for the high level subgroup, and 236 days for the low level subgroup (Figure 1). The 6-month survival rates were 22% and 54%, respectively. The subgroup with B2M level > 8.73 mg/L was older and had a higher proportion of stage IV. Patients with higher levels of B2M showed lower levels of platelets, albumin, and fibrinogen, and high levels of creatinine. A moderate correlation between creatinine and serum B2M was found (Spearman's ρ = 0.417, p < 0.001). The multivariate analysis showed that the high levels of serum B2M (> 8.73 mg/L) and creatinine (≥ 133 μmol/L), decreased fibrinogen (≤ 1.5 g/L), agranulocytosis (< 0.5×10 9/L), severe thrombocytopenia (< 50×10 9/L), and increased Epstein-Barr virus DNA were found to have significant prognostic values in all patients. The high serum B2M level (> 8.73 mg/L), severe thrombocytopenia (< 50×10 9/L), agranulocytosis (< 0.5×10 9/L), and high Epstein-Barr virus DNA copy number were independent prognostic factors in patients with creatinine < 133 μmol/L. Finally, a prognostic scoring system was established based on serum B2M levels as well as five other independent prognostic factors and divided the patients into three groups with significant prognostic differences (median survival: low-risk [score ≤ 1] 428 days vs. intermediate-risk [score = 2] 102 days vs. high-risk [score ≥ 3] 18 days, P < 0.0001) (Figure 2). The 6-month survival rates were 67%, 46% and 14%, respectively. Conclusions: This study confirmed that the serum B2M level could be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival.

Treatments and Outcomes of Lymphoma-Associated Hyperinflammation- a Report from the HLH in Adults Working Group for the Histiocyte Society

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome. Lymphoma is the most common cause of HLH in adults. Previous studies have indicated poor patient outcomes in lymphoma-associated HLH. The recently introduced optimized HLH inflammatory (OHI) index has improved prognostication and identification of the hyper-inflammatory phenotype of lymphoma; however, more comprehensive information on treatments and outcomes in a large cohort in the contemporary era is necessary. Our study aimed to investigate the clinical features, treatments, and outcomes of lymphoma-associated HLH through a multi-national effort by the HLH in Adults Working Group of the Histiocyte Society (NCT05898477). Methods: We conducted a multicenter, retrospective study evaluating patients diagnosed with lymphoma and hyperinflammation, defined by fulfilling 5/8 HLH diagnostic criteria or the OHI index from 2003-2022. Clinical characteristics were summarized using median and interquartile ranges (IQR). Survival analysis employed Kaplan-Meier curves and the log-rank test, considering HLH diagnosis as the zero time-point. Results: The analysis encompassed 181 patients with lymphoma: 55% had B-cell non-Hodgkin lymphoma (NHL), 35% had natural killer (NK) cell or T-cell lymphoma, and 10% had classical Hodgkin lymphoma. 35% of patients were from China, 21% from the USA, 17% from Israel, 16% from Europe, and 11% from Japan. Of the entire cohort, 157 (87%) patients met the HLH-2004 criteria, and 153 (83%) met the OHI index; The median age at HLH diagnosis was 60 years (IQR, 45-68), and 59% were males. 50% of patients presented with HLH before/at the time of lymphoma diagnosis (median time to lymphoma diagnosis 9 days), while 50% developed HLH after the initial lymphoma diagnosis (median time to HLH diagnosis 181 days). The median values of hemoglobin, absolute neutrophil count (ANC), and platelet count at HLH diagnosis were 8.6 g/dL, 2.1 K/microL, and 54.7 K/microL, respectively. The median values of triglycerides and fibrinogen were 241 mg/dL and 250 mg/dL, respectively. Interestingly, the median values for ANC, triglycerides, and fibrinogen fell outside the HLH-2004 diagnostic threshold. The median and interquartile ranges for ferritin and sCD25 (sIL-2r) were 3017 ng/mL (1337-8958) and 14098 U/mL (7894-39916), respectively. 48% of physicians altered their initial treatment approach due to the HLH diagnosis. Of these instances, 48% were treated with dexamethasone and etoposide outside of a formal treatment protocol, 11% with the HLH-94/2004 protocol, 24% with DEP regimen (liposomal doxorubicin, etoposide, and methylprednisolone), and 4% with DEP and ruxolitinib. Dexamethasone alone was used in 15% of the patients, while another 4% were treated with anakinra +/- steroids. After a median follow-up duration of 2.1y (range, 0.005-6.1), the median overall survival was 0.58 years. 46% of the patients died from multi-organ dysfunction/HLH, 17% from single-organ dysfunction, 16% from infection or septic shock, and 8% from bleeding. The risk of mortality among T-cell or NK cell lymphoma was higher than B-cell lymphoma (HR 1.7, 95% CI 1.16-2.61, Figure 1A). Finally, patients positive for the OHI index alone at diagnosis had a higher mortality risk (Figure 1B) compared to those positive for both the OHI index and HLH-2004 (HR 2.5; CI 1.26 - 4.8) or those positive for HLH-2004 alone (HR 3.72; CI- 1.62-8.58). Conclusions: Preliminary findings from this large multi-institutional study show that the overall survival for patients with lymphoma and HLH remains poor despite the institution of HLH-specific therapies. In nearly half of the cases, the physicians altered lymphoma treatment to control HLH, primarily through dexamethasone and etoposide-based or DEP regimens. Although B-cell lymphoma was our cohort's most common cause of HLH, overall survival was worse among those with T-cell or NK cell lymphoma, suggesting that the underlying lymphoma type might drive the prognosis even in cases with hyperinflammation. The most common causes of death included multi-organ dysfunction and infection. The OHI index-positive patients experienced higher mortality risk than those meeting the HLH-2004 criteria. The study is ongoing, and we plan to present data on the differential effects of treatment regimens at the meeting.

A Respective Analysis of EBV DNA Status in T/NK Cell Lymphoma Associated-Hemophagocytic Lymphohistiocytosis

Background: To explore the clinical characteristics and prognostic implication of Epstein-Barr virus (EBV) DNA status in patients with T-cell or natural-killer cell lymphoma-associated hemophagocytic lymphohistiocytosis (T/NK-LAHLH). Method: Patients who diagnosed with T/NK-LAHLH in the First Affiliated Hospital of Zhejiang University from January 2017 to August 2022 were included. Baseline characteristics were summarized and compared. Complete response (CR), partial response (PR) and no response (NR) were used to evaluate the 2-week efficacy of HLH treatment. Overall survival (OS) was estimated by Kaplan-Meier method and log-rank test. Cox proportional hazard model for potential factors were conducted. Result: Eight-five T/NK-LAHLH patients were finally enrolled, with a median age of 52 (18-81) years. According to EBV DNA status, sixty-seven were classified as EBV DNA positive group and 18 were EBV DNA negative group. Patients in EBV DNA positive T/NK-LAHLH group displayed significantly lower PLT (P=0.003), and globulin level (P=0.033), higher IL-10 level (P=0.011) and longer activated partial thromboplastin time (APTT, P=0.034) than those of EBV DNA negative T/NK-LAHLH group at HLH diagnosed. For patients received the anti-HLH therapy only, the ORR was 33.9%, patients in the liposomal doxorubicin-etoposide-prednisolone (DEP) group and ruxolitinib combined with corticosteroid (Ru-D) group achieved relatively better efficacy, with ORR 56.3% and 64.3%, respectively. Whereas the ORR in the HLH-94 group was 23.1% and corticosteroid with or without intravenous immunoglobulins (GC±IVIG) regimen had no effect on T/NK-LAHLH, all patients showed no response to GC±IVIG regimen. The difference of ORR was significance among the four anti-HLH regimens (P<0.001). The median period of anti-HLH therapy was 5 days for patients who received anti-HLH therapy and then switched to anti-lymphoma chemotherapy, with ORR 78.3%. There was a significant difference in the efficacy and OS for whether converted to anti-lymphoma therapy within 2 weeks after receiving anti-HLH (P<0.001 and P=0.018, respectively). Patients who obtained HLH control within 2 weeks have a better OS (P<0.0001) than no response to therapy. EBV DNA-positive patients displayed significantly worse OS than EBV DNA-negative patients (P<0.0001). Furthermore, all 5 patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were still alive during the follow-up period and achieved significantly prolonged survival (P=0.013) than those who did not. By multivariate analysis, EBV DNA positive, advanced age, prolonged APTT, elevated fibrinogen level and no response to HLH treatment were independent risk factors of OS. Conclusion: EBV infection, along with coagulation abnormalities, advanced age and no response to HLH therapy were independent prognostic factors for patients with T/NK-LAHLH. Early diagnosis and appropriate chemotherapy plus HSCT are essential to achieve improved outcomes in T/NK-LAHLH patients. Keywords ：hemophagocytic lymphohistiocytosis, T/NK cell lymphoma, EBV, HSCT, treatment, prognosis

Differences in Diagnostic Characteristics and Outcomes in Adults with Malignancy-Associated and Non-Malignancy-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by life-threatening inflammation. In adults, roughly 50% of HLH manifests in association with an underlying malignancy (most commonly lymphoma), and the remaining cases are due to infection, autoimmune disease, late presentations of genetically-driven HLH, and sometimes multifactorial or idiopathic causes. Although the majority of prospective data for HLH are derived from children, survival outcomes for non-malignant causes of adult HLH (nmHLH) are thought to rival pediatric HLH; however, outcomes for malignancy-associated HLH (mHLH) appear to be substantially worse (~10-30% 5-year overall survival) in the literature. As diagnostic and prognostic models for HLH outcomes have primarily been constructed using pediatric data, attempts have been made to develop diagnostic indices applicable to adult HLH (particularly mHLH). Here, we summarize the clinical and laboratory characteristics of mHLH and nmHLH in a retrospective observational study, and evaluate the role for common diagnostic tools for adult HLH. Methods: Patients >18 years old, fulfilling at least five of the HLH-2004 diagnostic criteria with at least 3 months of follow-up (among survivors) were enrolled. All included patients received definitive HLH therapy, including cancer-directed therapy when appropriate, but those receiving only systemic steroids were excluded. Treatment-related HLH, such as HLH occurring with immune effector cell therapy or hematopoietic cell transplantation, was excluded. Clinical and laboratory parameters reflect the most recent values on or prior to diagnosis and treatment initiation. Differences between mHLH and nmHLH were assessed with two-tailed t-test or Wilcoxon test. Survival outcomes are estimated by Kaplan-Meier. Multivariate analysis was performed using Cox proportional hazards and compared using logrank test. Results: 42 adults were diagnosed with HLH requiring HLH-specific therapy (23 mHLH, 19 nmHLH) between 3/2016 and 3/2023 with a median age of 50 (range 21-75). Of the mHLH cases, 44% were due to T/NK cell lymphomas; 52% were B cell lymphomas including 26% Hodgkin. Of the nmHLH cases, most were due to infection (47%); while others were deemed to be idiopathic (26%) or genetic (16%). All patients with mHLH had fever (v 84% in nmHLH); 91% met cytopenia criteria (v 68%), and absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet count (plt) were all statistically lower than in nmHLH (mean ANC 3.2 v 11.3; Hgb 7.8 v 8.5; plt 43 v 88; p<0.05). Mean soluble interleukin-2 (sIL2) level was significantly higher in mHLH (39,579 pg/mL v 18,484) after adjusting for a single outlier. All other HLH-2004 diagnostic parameters were not statistically different between mHLH and nmHLH, including ferritin and sIL2/ferritin index. All mHLH patients had an underlying lymphoma and met the optimized HLH inflammatory (OHI) index except a single patient with leukemia; 4 patients with nmHLH did not meet the OHI index. In 79% of patients, the HLH94 regimen was incorporated in the induction regimen; the remaining utilized chemotherapy or antibiotics, with and without adjunctive steroids. 4 cases proceeded to allogeneic transplantation. Relapse rates were high, with median relapse-free survival (RFS) being 37 days (23 v 47 days for mHLH and nmHLH, respectively); median overall survival (OS) was 96 days (86 v 149 days). RFS/OS was not statistically different between mHLH and nmHLH. Age was a significant predictor of OS but not RFS; no other diagnostic parameter was predictive, including degree of ferritin or sIL2 elevation. 13 patients were alive at the time of last follow-up (6 mHLH, 7 nmHLH). Conclusions: In this single center retrospective study, both mHLH and nmHLH requiring HLH-directed therapy demonstrated poor survival outcomes in adults. The degree of cytopenias and sIL2 elevation were more significant in mHLH in comparison with nmHLH. The OHI index identified all cases of lymphoma-associated HLH but neither ferritin nor sIL2 levels were predictive of survival. These data emphasize the need for therapeutic advances for management of adults with mHLH and nmHLH and continued optimization of diagnostic criteria for adult HLH.

Clinical Features and Outcomes of Hemophagocytic Lymphohistiocytosis Secondary to Lymphoma: Insights from a Tertiary Center in Saudi Arabia

Introduction: Lymphoma encompasses a prominent cause of secondary hemophagocytic lymphohistiocytosis (HLH), an aggressive hyperinflammatory syndrome characterized by immune dysregulation. The concurrence of lymphoma and HLH represents a challenging entity due to the ambiguity of clinical features and paucity of standardized treatment regimens. Limited data exists regarding the characteristics and outcomes of secondary HLH within the Middle East and Saudi Arabia. Moreover, the structure of the population within our region, characterized by a predominance of males and young adults, offers a unique perspective to the literature regarding secondary HLH. Herein, we evaluate the clinical features and outcomes of patients presenting with HLH secondary to lymphoma at a tertiary center in Saudi Arabia. Methods: We retrospectively reviewed the electronic medical records of patients diagnosed with lymphoma over the past ten years at our center to identify patients who developed secondary HLH. The Kaplan-Meier method was used to estimate median overall survival (OS). OS was defined as the incidence of death from any cause from the onset of HLH diagnosis until the end of follow-up. The Cox proportional hazards model was used to identify demographic, clinical, and treatment associated prognostic indicators which had a significant impact on OS. Results: A total of 1484 patients with lymphoma were identified, of which seventeen (1.1%) patients had concurrent HLH. Of the seventeen patients, the median age was 42 years (range 17-64) with 5 (29.4%) patients aged 50 and over. Interestingly, all 17 (100.0%) patients within our cohort were male. Regarding lymphoma subtypes, 10 (58.8%) patients had T and NK-cell lymphoma, 5 (29.4%) had B -cell lymphoma, and 2 (11.7%) had Hodgkin lymphoma. The median HScore was 272.0 (range 182-337) whereas the median HLH-2004 diagnostic criteria score was 6 out of 8 points (range 4-8). Hemophagocytic features in the bone marrow were present in 13 (76.5%) patients. Epstein-Barr virus infection was detected in 9 (52.9%) patients with a median quantitative PCR level of 37347.5 IU/mL (range 1960.0-402847.0). HLH therapy utilized in our patient sample included corticosteroids in 15 (88.2%) patients, etoposide in 8 (47.1%) patients, and intravenous immunoglobulin in 3 (17.6%) patients. Death occurred in 7 (41.2%) patients whilst the median OS of the cohort was 13.0 months (95% CI 0.0-27.4). Using the cox proportional hazards model, both age ≤50 years (P=0.04, hazard ratio=0.186) and etoposide administration (P=0.002, hazard ratio=0.011) were associated with significantly improved survival. Conclusions: To our knowledge, this is the first cohort study reporting the clinical features and outcomes of HLH secondary to lymphoma within our region. Our study highlights the significant disparities between our population and other countries across the globe as our cohort demonstrated a significant male predominance as well as a relatively young median age at diagnosis. Nonetheless, the survival outcomes of secondary HLH remain poor despite the advances in the diagnostication and recognition of the disease. Future efforts ought to explore both the pathophysiological mechanisms underlying lymphoma-associated HLH and the efficacy of different targeted therapeutic modalities.

The Clinical Significance and Prognostic Role of Whole-Blood Epstein-Barr Virus DNA in Lymphoma-Associated Hemophagocytic Lymphohistiocytosis.

To evaluate the role of circulating Epstein-Barr virus (EBV) DNA in lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). We conducted a retrospective cohort study to explore the clinical and prognostic significance of EBV DNA in lymphoma-associated HLH. We included adult patients with combined diagnoses of lymphoma and HLH from January 2010 and November 2022 by retrieving the medical record system. A total of 281 patients with lymphoma-associated HLH were identified. Elevated whole-blood EBV DNA was observed in 54.4% (153/281) of patients, and the median copy number was significantly higher in the T/NK-cell malignancies (199,500, interquartile range, 30,000-1,390,000) than that in the B-cell non-Hodgkin lymphoma (5520, interquartile range, 1240-28,400, P < 0.001). The optimum cutoff for predicting survival was 16,100 copies/mL. Compared to the patients with EBV DNA ≤ 16,100 copies/mL, those with EBV DNA > 16,100 copies/mL were younger and had more T/NK-cell malignancies, lower levels of neutrophils and fibrinogen, and higher levels of hemoglobin, alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, and β2-microglobulin. A higher load of EBV DNA (> 16,100 copies/mL), thrombocytopenia (< 100 × 109/L), neutropenia (< 1 × 109/L), hypofibrinogenemia (≤ 1.5g/L), and elevated levels of creatinine (> 133μmol/L) were independent adverse predictors of 60-day overall survival and overall survival. A prognostic index based on EBV DNA and the other four factors was established to categorize the patients into four groups with significantly different outcomes. Our study identified high EBV load as a risk factor for lymphoma-associated HLH and established a prognostic index to predict outcomes.

Combination of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED) in treatment of advanced extranodal NK/T-cell lymphoma.

Combination of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED) in treatment of advanced extranodal NK/T-cell lymphoma.

Characteristics and prognosis of distant metastasis after primary treatment for early-stage extranodal nasal-type natural killer/T-cell lymphoma from the China Lymphoma Collaborative Group database.

This study aimed to investigate the characteristics and prognosis of distant metastasis (DM) after primary treatment for early-stage extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTCL). A total of 1619 patients from the China Lymphoma Collaborative Group database were retrospectively reviewed. The cumulative incidence of DM was assessed using Fine and Gray's competing risk analysis. The correlation between DM sites was evaluated using phi coefficients, while DM sites were classified using hierarchical clustering. Regression analysis was used to assess the linear correlation between DM-free survival (DMFS) and overall survival (OS). The 5-year cumulative DM rate was 26.2%, with the highest annual hazard rate being in the first year (14.9%). The most frequent DM sites were the skin and soft tissues (SSTs, 32.4%) and distant lymph nodes (LNs, 31.3%). DM sites were categorized into four subgroups of distinct prognosis - distant LN, SST, extracutaneous site, and lymphoma-associated hemophagocytic lymphohistiocytosis. SST or distant LN, solitary metastasis, and late-onset DM demonstrated a relatively favorable prognosis. Contemporary chemotherapy significantly decreased DM rates and improved DMFS. Decreased DM rates were further associated with increased OS probabilities. Our findings improve the understanding of the variable clinical behaviors of early-stage ENKTCL based on four distinct DM sites and thus provide guidance for future therapeutic decisions, metastatic surveillance, and translational trial design.

Pattern and Prognosis of Distant Metastases in Patients with Early-Stage Extranodal Nasal-Type NK/T-Cell Lymphoma

<h3>Purpose/Objective(s)</h3> This study investigated the failure pattern and prognosis of distant metastasis for early-stage extranodal nasal-type natural killer/T-cell lymphoma (ENKTCL). <h3>Materials/Methods</h3> 1619 patients with complete information on distant metastatic sites were identified. The distribution of distant metastatic sites was reported. The distant metastatic sites were categorized into 4 groups. The overall survival (OS) and subsequent OS of the 4 groups were compared. The effect of distant metastatic number and time on subsequent OS were evaluated. <h3>Results</h3> DM was the primary mode of failure in this cohort, with a 5-year cumulative of 26.2%. The most frequent distant metastatic site was skin and soft tissue (SST, 32.4%), followed by distant lymph node (LN, 31.1%), lung (17.3%), liver (14.6%), lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS, 10.7%) and gastrointestinal system (10.4%). While central nervous system, spleen, urogenital system, adrenal glands, bone, bone marrow and pancreas involvements were less common. The distant metastatic sites were categorized in to 4 groups: distant LN, SST, other sites and LAHS. The 4 categories demonstrated distinct OS and subsequent OS, with decreased mortality for distant LN and SST compared with other sites and LAHS. Besides, solitary DM and late DM (> 7.5 months) were associated with favorable 3-year OS compared with multiple metastases (45.7% versus 8.7%, P < 0.001) and early DM (≤ 7.5 months; 25.8% versus 15.8%, P = 0.001). <h3>Conclusion</h3> The findings were helpful understanding the variation in biology of different sites of metastases in patients with early-stage ENKTCL and provided important information for future therapeutic decisions, metastatic surveillance and translational studies.

Clinical characteristics and treatment of NK/T-cell lymphoma-associated HLH.

Natural killer (NK)/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHLH) is a rare and life-threatening disorder. Its clinical characteristics and appropriate treatment options are unclear. This study aimed to investigate the clinical characteristics and treatment options for this disease. We retrospectively analyzed the clinical data of 84 patients with NK/T-cell lymphoma and compared the characteristics, treatment, and survival between patients with and without HLH. Patients in the NK/T-LAHLH group were more likely to be younger age and have hepatosplenomegaly, B symptoms, neutropenia, anemia, thrombocytopenia, elevated lactate dehydrogenase levels, reduced serum albumin levels, bone marrow involvement, Ann Arbor stage III/IV, and International Prognostic Index score ≥ 3. After multivariate analysis, it was found that elevated lactate dehydrogenase and Ann Arbor stage III/IV were risk factors for HLH in patients with NK/T-cell lymphoma. After 2weeks of therapy, 78.6% (11/14) patients who received the L-DEP/DEP regimen achieved an overall response rate of HLH, which was higher than that in 42.9% (9/21) patients who received the VP-16 + dexamethasone-based regimen. NK/T-LAHLH patients had poorer survival than non-HLH-NK/TCL patients. For NK/T-LAHLH, the L-DEP/DEP regimen may have a better response rate than the VP-16 + dexamethasone-based regimens.

Modified DEP regimen as induction therapy for lymphoma-associated hemophagocytic lymphohistiocytosis: a prospective, multicenter study.

Hemophagocytic lymphohistiocytosis (HLH), especially lymphoma-associated HLH (LA-HLH), is a refractory immune disorder with high mortality. There is still no consensus regarding the ideal treatment for LA-HLH. We performed a prospective multicenter study (NCT04077905) to explore the efficacy of a modified DEP regimen as induction therapy for LA-HLH. Twenty-eight patients from 6 clinical centers in China were enrolled between September 2019 and July 2021. We evaluated the efficacy of the modified DEP induction therapy 4 weeks after the initiation of treatment. The results showed that the overall response rate was 89.3% (25/28 patients), whereby 28.6% (8/28 patients) achieved a complete response and 60.7% (17/28 patients) were in partial response. Ferritin and soluble CD25 levels were decreased significantly 4 weeks after the modified DEP induction therapy (P = 0.001 and P = 0.00016, respectively), while platelet count and total bilirubin improved significantly (P = 0.004 and P = 0.001, respectively). The 1-year overall survival rate of all patients was 34.5%, with a median survival of 6.5months (range 0.5-19months). Patients with LA-HLH who underwent a stem cell transplantation had a significantly better prognosis than those not achieving complete response 4 weeks after modified DEP induction therapy (P = 0.034). Our study suggests that the modified DEP regimen is a safe and effective induction therapy for LA-HLH. Timely stem cell transplantation can improve the prognosis of patients with LA-HLH. NCT04077905. URL: https://clinicaltrials.gov/ct2/show/NCT04077905?id=NCT04077905&draw=2&rank=1 .

The emerging role of anti-PD-1 antibody-based regimens in the treatment of extranodal NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis.

Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients. The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not. The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6months (range 0-65.9months), the median overall survival (mOS) was 3.5months (95% CI：2.3-4.7months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2months (95% CI: 2.5-7.8months) vs. 1.5months (95% CI: 0.5-2.6months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients. In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population.

Interpretation of Chinese expert consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with lymphoma (2022)

Chinese expert consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis (HLH) associated with lymphoma was revised on the basis of evidence-based medical evidence in combination with domestic and international research progress. It added the classification of "according to the difference in the causes of HLH". For the first time, the revised version included the classification of lymphoma-associated HLH induced by immunotherapy. The contents of genetic background defects and central nervous system involvement in lymphoma-associated HLH were also supplemented. This article gives a detailed interpretation of the updated content in the consensus.

P1243: RUXOLITINIB COMBINED WITH DEXAMETHASONE IN ADULT PATIENTS WITH NEWLY DIAGNOSED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: INTERIM ANALYSIS OF A PROSPECTIVE, SINGLE-CENTER, SINGLE-ARM, PHASE 2 CLINICAL TRIAL

Background: Hemophagocytic lymphohistiocytosis (HLH) in adults is a major clinical challenge due to its rapid progress and high mortality. The current first-line therapy strategies such as HLH-94 or HLH-2004 regimens are largely extrapolated from paediatric HLH; however, the prognosis of adult HLH is worse than that of children. Ruxolitinib (an oral JAK inhibitor) has shown favorable efficacy and safety in murine models and clinical trials in adult HLH. Moreover, Lauren K. Meyer et al. demonstrate that ruxolitinib can reverse the resistance of CD8 positive T cells to dexamethasone in hypercytokinemia of HLH. We were very interested in these results and preliminarily revealed the high response rate and good short-term survival of ruxolitinib combined with dexamethasone (Ru-D) in a pilot study involving 8 adult HLH patients. On these bases, we conducted this prospective, single-center, single-arm, Phase 2 clinical study. Aims: This phase 2 clinical trial (ChiCTR2100049996) aims to evaluate the efficacy and safety of Ru-D regimen as first-line therapy in adults with newly diagnosed HLH. Methods: This is an interim analysis of an ongoing phase 2 clinical trial of a planned 28 newly diagnosed adult HLH patients. Inclusion criteria were patients who met HLH-2004 diagnostic criteria, older than 18 years old, and had not received HLH first-line therapy. Patients in this study received an 8-week period of treatment. The Ru-D regimen consists of ruxolitinib (15 mg twice daily for 8 weeks) and dexamethasone (initially 10 mg/m2 for 2 weeks followed by 5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks, 1.25 mg/m2 for one week, and one week of tapering). The primary endpoint is the 2-month overall survival rate (OS), and the secondary endpoints are overall response rate (ORR), progression-free survival (PFS), safety and changes in biomarkers. Results: From August 15, 2021 to January 15, 2022, there were 15 patients enrolled in this study with a median follow-up of 78 (31-171) days. The 15 patients included 8 cases of lymphoma-associated HLH (LAHS), five case of Epstein-Barr virus-associated HLH (EBV-HLH), and 2 cases of unknown etiology. It should be mentioned that 4 of 15 patients carried heterozygous HLH-related gene mutations. Patients were followed up until February 15, 2022 or until death, with none lost to follow-up. The primary endpoint, 2-month OS, was 83.3% in 12 evaluable patients, both patients died due to lymphoma progression. The overall mortality rate was 26.7% (4/15), 75% (3/4) deaths occurred in LAHS patients and there was no death directly related to HLH until data cutoff. The ORR to Ru-D regime was 86.7% (13/15), with 13.3% (2/15) in complete response (CR), 73.3% (11/15) in partial response (PR), and 13.3% (2/15) in no response (NR). The treatment was well tolerated, with no toxicities leading to dose reduction or discontinuation of treatment. All LAHS patients were successfully bridged to chemotherapy after Ru-D therapy. Table 1 shows the response outcomes in detail. Image:Summary/Conclusion: In our study, the Ru-D regimen initially demonstrated favorable efficacy in newly diagnosed adult patients with HLH. For patients with LAHS, it is an efficient and safe bridging therapy while waiting for pathological diagnosis. Therefore, Ru-D represents a novel and promising therapeutic option for HLH patients that may provide clinical benefit.

Nasal type extranodal natural killer/T-cell lymphomaassociated hemophagocytic lymphohistiocytosis: A Case report and literature review

Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome in which a large number of inflammatory cytokines, such as IL-6, TNF-α, and sCD25, are released into the blood circulation due to cytotoxic killing cells and dysfunction of natural killer (NK) cells. HLH can be induced by various infections, cancer, or hereditary disorders. HLH is usually fatal due to severe cytopenia and multiple organ failure. Nasal type extranodal natural killer/T-cell lymphoma (ENKTCL) is an aggressive non-Hodgkin’s lymphoma that is closely related to Epstein-Barr virus. ENKTCL can be complicated by HLH at initial diagnosis and recurrence. However, the optimal treatment strategies for ENKTCL-associated HLH are not well defined. Here, we report a case of ENKTCL-associated HLH that was successfully treated with liposomal doxorubicin, etoposide, methylprednisolone, and pegaspargase (DEPL regimen), followed by immunotherapy. This report aims to contribute to improved recognition, diagnosis, and treatment of lymphoma-associated HLH. Keywords: Hemophagocytic lymphohistiocytosis, extranodal natural killer/T-cell lymphoma, liposomal doxorubicin, pegaspargase, lymphoma-associated HLH

Monitoring coagulation-fibrinolysis activation prompted timely diagnosis of hemophagocytic lymphohistiocytosis-related disseminated intravascular coagulation

BackgroundTimely diagnosis of disseminated intravascular coagulation (DIC) in hemophagocytic lymphohistiocytosis (HLH) patients is crucial but challenging, as HLH interferes with the results of the laboratory tests included in the DIC score system.Case presentationHere, we reported a case of lymphoma-associated HLH, in which coagulation-fibrinolysis activation /inhibition markers (TAT, tPAIC, and PIC), prompted timely diagnosis of early stage DIC (initial phase of microvascular thrombosis, yet non-overt), prior to the development of organ failures and/or bleedings.ConclusionsThis report highlights the importance of the implementation of new biomarkers (such as TAT, tPAIC, and PIC), into the diagnostic work-up for coagulation disorders. These biomarkers are directly suggestive of microthrombus formation, therefore they can be of paramount importance in diagnosing DIC with complicated etiologies, such as hematological diseases-related DIC.