“Optimizing” HLH diagnoses in patients with lymphoma Open Access

In this issue of Blood Advances, Zoref-Lorenz et al¹ delve further into the optimized hemophagocytic lymphohistiocytosis (HLH) inflammatory (OHI) index, a pioneering prognostic tool aimed at identifying newly diagnosed patients with lymphoma burdened by hyperinflammation and an increased risk of mortality.

Secondary HLH (sHLH) is a life-threatening disease marked by severe immune dysregulation, leading to recurrent fevers, progressive pancytopenia, coagulopathy, and irreversible multiorgan deterioration. Unlike familial HLH, which arises due to inherited defects in cytotoxicity, sHLH is an acquired phenomenon triggered by underlying diseases, such as malignancies, infections, autoimmune disorders, immune deficiencies, or complications related to immunotherapy, including those associated with chimeric antigen receptor T-cell therapy, bispecific antibodies, and checkpoint inhibitors. In adults, malignancy-associated HLH (mHLH) prevails as the dominant etiology, exhibiting a dismal prognosis with a median survival of <6 months.^2-4 However, the absence of universally recognized diagnostic criteria and biomarkers for mHLH has complicated efforts to accurately identify and effectively treat the most vulnerable individuals facing inflammation-related mortality.

Traditional diagnostic models, such as the HLH-2004 criteria and HScore, often lack sensitivity in the setting of hematologic malignancies (HMs) due to the cancer’s direct impact on laboratory parameters, rendering them imprecise for selecting patients who may benefit from alternative therapeutic approaches.⁵ Symptoms such as organomegaly, fevers, pancytopenia, and mild hyperferritinemia frequently manifest in both sHLH and aggressive HMs, causing significant diagnostic ambiguity. The OHI index was optimized to fine-tune patient stratification by eliminating potentially confounded objective data that obscure the distinctions between advanced HMs vs an actual sHLH pathophysiological entity. By integrating biomarker proxies for macrophage activation (eg, ferritin) and activated T cells (eg, sCD25), the OHI index distinguishes patients grappling with extreme immune-driven inflammation, surpassing the capabilities of conventional lymphoma prognostic frameworks and HLH classification models in this unique patient population.⁶ 

Alternative prognostic systems, such as the OHI index pioneered by Zoref-Lorenz et al, demonstrate promising capabilities in enhancing the evaluation of patients with lymphoma and improving the predictive accuracy of early mortality. Throughout their investigation, OHI+ patients (sCD25 >3900 U/mL and ferritin >1000 ng/mL) endured dramatically inferior survival outcomes relative to OHI– patients. One-year overall survival (OS) rates plummeted to 33% in OHI+ patients, compared to 81% in OHI– patients, with a median OS of merely 190 days in the OHI+ cohort, whereas it remained unreached in OHI– patients. The disparities widened over the 3 years, with OHI+ patients exhibiting an OS rate of just 23%, contrasted with 80% in OHI– patients, alongside a staggering 13-fold increase in mortality risk, a phenomenon unaccounted for through conventional lymphoma indices, such as the International Prognostic Index (IPI). Although IPI-predicted OS remained similar between OHI+ and OHI– patients, observed survival outcomes were markedly poorer in the OHI+ subgroup, emphasizing the role of immune-driven hyperinflammation as a principal determinant of mortality.

This observation is striking and has significant clinical and pathogenic implications. From a clinical perspective, OHI+ patients demonstrated a propensity for aggressive disease traits compared to their OHI– counterparts. Advanced-stage lymphoma was significantly more prevalent among OHI+ patients (77% vs 50%), reinforcing their disease burden, which potentially contributes to more chronic T-cell activation driving the elevated sCD25 levels. Consistent with this advanced disease and inflammatory burden, functional performance scores were lower, with 32% of OHI+ patients falling within Eastern Cooperative Oncology Group (ECOG) performance status 3 to 4, vs only 17% of OHI– patients. In contrast, 35% of OHI+ patients maintained an ECOG score of 0 to 1, compared to 61% of OHI– patients, indicating a higher level of systemic deterioration within the OHI+ cohort. Interestingly, although extranodal disease remained comparable, the specific sites varied, with bone marrow infiltration being significantly heightened in OHI+ patients (55% vs 15%), whereas OHI– patients exhibited more significant central nervous system, skin, and bowel infiltration. It is possible to speculate that the presence of malignancy within the bone marrow could drive more potent macrophage activation and potentially a more HLH-like inflammatory state. However, these hypotheses require further detailed investigation. Despite the striking morphological distinctions, molecular subtypes within diffuse large B-cell lymphoma showed no meaningful OS difference, indicating that OHI status operates independently of current lymphoma classification systems.

Mortality patterns further reinforced the inflammatory signature of OHI+ patients. Over the 3-year follow-up, OHI+ patients accounted for 50 deaths, whereas OHI– patients experienced only 14 fatalities. Unlike OHI– patients, for whom lymphoma progression emerged as the primary proximate cause of death (70%), OHI+ patients primarily succumbed to multiorgan failure, which contributed to 58% of deaths. These observations implicate a role for chronic T-cell hyperactivation in mortality, a mechanism also observed in primary HLH (pHLH) and sHLH from nonmalignant triggers. This hypothesis is supported by the beneficial role of incorporating etoposide into treatment regimens in the OHI+ population. Etoposide is effective in pHLH due to its efficacy in eliminating activated and proliferating T cells, and its use may also provide benefits in OHI+ patients with lymphoma. However, key questions remain, including the antigen specificity of these activated T-cell populations. If they are providing antitumor responses, then dampening their activation state with less potent therapies could be more beneficial than eliminating them. These findings highlight the intricate interplay between immunologic dysfunction and inflammation-induced morbidity in this complex patient population, underscoring the need for further investigation.

In summary, the OHI index identifies a distinct subgroup of newly diagnosed patients with lymphoma characterized by immune-driven hyperinflammation, aggressive systemic involvement, and dismal survival rates, which are often unrecognized by traditional lymphoma classifications. These findings highlight the critical role of T-cell– and interferon gamma–mediated inflammation, underscoring the therapeutic potential of targeting this pathway in an appropriately selected patient population. Further research into novel treatment approaches, including the use of targeted, precision-based treatment paradigms for high-risk OHI+ patients with lymphoma, remains warranted.

Conflict-of-interest disclosure: W.T.J. reports consulting fees from BioNTech, Sobi, and Electra Therapeutics. J.M.R. declares no competing financial interests.