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

Abstract

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.

Fig. 1

PRISMA flow diagram showing study selection process.

Fig. 2. Map showing the geographic distribution of N = 542 reported patients and corresponding lymphoma subgroups.

Abbreviations: B-NHL B-cell non-Hodgkin lymphoma, T-NHL T-cell non-Hodgkin lymphoma, HL Hodgkin’s lymphoma.

Fig. 3. Distribution of HLH-triggering lymphoma subtypes. Two patients had HLH due to not further specified lymphoma.

Abbreviations: B-NHL B-cell non-Hodgkin lymphoma, T-NHL T-cell non-Hodgkin lymphoma, HL Hodgkin’s lymphoma, PTCL, NOS Peripheral T-cell lymphoma, not otherwise specified, SPTCL Subcutaneous panniculitis-like T-cell lymphoma, ENKTCL, NT Extranodal natural killer/T-cell lymphoma, nasal type, NKTCL Natural killer/T-cell lymphoma, AITL Angioimmunoblastic T-cell lymphoma, ALCL Anaplastic large-cell lymphoma, DLBCL Diffuse large B-cell lymphoma, BCL, NOS B-cell lymphoma, not otherwise specified, MZL Marginal zone lymphoma, CLL Chronic lymphocytic leukemia, LPL Lymphoplasmacytic lymphoma, HGBCL High-grade B-cell lymphoma, MCL Mantle cell lymphoma.

Fig. 4. Kaplan-Meier plots displaying estimated survival.

Kaplan-Meier plots displaying estimated survival. Plot (a) shows information for the entire cohort, (b) for lymphoma subgroups, and (c) for patients who had received any lymphoma-specific treatment depending on lymphoma subgroup. Abbreviations: LA-HLH lymphoma-associated hemophagocytic lymphohistiocytosis, B-NHL B-cell non-Hodgkin lymphoma, T-NHL T-cell non-Hodgkin lymphoma, HL Hodgkin’s lymphoma, NKTCL natural killer/T-cell lymphoma.

Fig. 5. Multivariate Cox regression analysis for possible prognostic factors.

Multivariate Cox regression analysis for possible prognostic factors. Results are presented as Forest plots with Hazard ratios and confidence intervals, plots provide information on (a) overall mortality and (b) 30-day mortality (death within 30 days). Abbreviations: HR hazard ratio, CI confidence interval, sCD25 soluble CD25.