Acute Clinical Syndrome of HLH in Patients with Hematologic Malignancy and EBV Infection

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by dysregulation of the reticuloendothelial system, overactivation of macrophages and lymphocytes, hemophagocytosis, and cytokine storm collectively causing systemic inflammation and organ damage. Malignancy-associated HLH (M-HLH) is associated with poor prognosis and survival of 1-2 months (Daver N, et.al., Cancer. 2017). Viral infections such as Epstein-Barr Virus (EBV) can independently contribute to development of lymphoproliferative neoplasms and non-malignancy associated HLH. While both malignancy and EBV are recognized as independent risk factors for HLH, a syndrome of overlapping M-HLH and EBV-HLH remains underreported. The optimal long-term treatment strategy for M-HLH in EBV positive patients is unknown, with combinations of HLH and malignancy directed therapy reported in the literature without significant improvement in survival (Zhao A, et.al., Front Immunol. 2022). We report a case series of patients with EBV infection and newly diagnosed hematologic malignancies complicated by HLH demonstrating poor prognosis despite initial control of disease.

Methods: Between July 2020 and July 2021, 8 patients >18 years of age hospitalized at Montefiore Medical Center were identified meeting diagnostic criteria of HLH with associated primary hematologic malignancy, and concomitant EBV infection. Data on demographics and clinical characteristics, laboratory studies, malignancy diagnosis, treatments received, and disease course were collected. HLH-04, H-Score were recorded for all patients. Data were analyzed using descriptive statistics.

Results: The median age was 53.6 years old (range 29-75). Five out of 8 patients met systemic inflammatory response syndrome (SIRS) criteria on presentation. The median H-Score was 217.1 (range 183-247). All but one patient exceeded CD25 and ferritin parameters of optimized HLH inflammatory (OHI) index suggestive of high mortality risk. Classical Hodgkin Lymphoma (cHL) was seen in 4/8 patients; other diagnoses included large B cell lymphoma, angioimmunoblastic T cell lymphoma, intravascular large B cell lymphoma, and anaplastic large cell lymphoma.

Dexamethasone was the backbone of treatment and the initial HLH directed therapy in all patients, starting on average 9 days after presentation (range 2-17) and preceding treatment with other HLH directed therapies by median of 7.2 days (range 0-33). Four out of 8 patients received dexamethasone, etoposide, and rituximab; 2 patients received dexamethasone with etoposide and 2 received dexamethasone alone. The administration schedule and cumulative doses of both rituximab and etoposide varied significantly between the patients. Initiation of malignancy directed chemotherapy lagged the initiation of dexamethasone by median of 16.5 days (range 0-53). Delays were due to patients' clinical condition, organ function, and pending diagnosis of malignancy.

Median overall survival from the initial presentation was 102.5 days (range 33-219). Two out of 8 patients in our case series survived. One received dexamethasone and etoposide, followed by 6 cycles of malignancy-directed chemotherapy and autologous stem cell transplant. The second patient was treated with dexamethasone, rituximab, etoposide with addition of anakinra, followed by malignancy directed therapy without rituximab or etoposide. At the time of death, 4 out of 6 patients had active HLH and 3 out of 6 patients were treated for an overwhelming polymicrobial infection.

Conclusion: HLH is the setting of EBV-positive malignancy results in a syndrome with an aggressive clinical course and high early mortality rate. Here we demonstrate that HLH-directed therapy prior to or incorporated into malignancy-directed therapy extended patients' survival to median 3 months, as compared to 1-2 months reported in the literature. Nevertheless, most patients suffered HLH relapse and succumbed to infectious complications of prolonged hospitalization and immunosuppression. Long term HLH therapy with immunomodulatory agents and EBV-directed therapies is needed to achieve sustained control of systemic inflammation. Patients who survive initial HLH episode need to be closely monitored for recurrence. Preemptive strategies such as autologous stem cell transplant should be considered in eligible patients to further reduce the risk of relapse.

Murakhovskaya:Sanofi: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Kezar: Research Funding; Annexon: Research Funding; Alexion: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Research Funding. Verma:BMS: Research Funding; Incyte: Research Funding; Jannsen: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Stelexis Therapeutics: Consultancy; MedPacto: Research Funding; GlaxoSmithKline: Research Funding; Stelexis Therapeutics: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Acceleron Pharma: Consultancy; Curis: Research Funding; Eli Lilly and Company: Research Funding.