Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe, dysregulated inflammation driven by the inability of T cells to clear an antigenic target. When associated with malignancy (mHLH), the HLH syndrome is typically associated with extremely poor survival. Here, we review the diagnosis of secondary HLH (sHLH) syndromes in adults, with emphasis on the appropriate workup and treatment of mHLH. At present, the management of HLH in adults, including most forms of mHLH, is based on the use of corticosteroids and etoposide following the HLH-94 regimen. In some cases, this therapeutic approach may be cohesively incorporated into malignancy-directed therapy, while in other cases, the decision about whether to treat HLH prior to initiating other therapies may be more complicated. Recent studies exploring the efficacy of other agents in HLH, in particular ruxolitinib, offer hope for better outcomes in the management of mHLH. Considerations for the management of lymphoma-associated mHLH, as well as other forms of mHLH and immunotherapy treatment-related HLH, are discussed.

Keywords: HLH; LAHS; hemophagocytic lymphohistiocytosis; hemophagocytosis; mHLH; ruxolitinib.

Figure 1

Pathophysiology of HLH [16]. Primary HLH is driven by genetic defects in T or NK cell cytotoxicity, while sHLH is driven by immune hyperactivation against an antigenic trigger. Clinical manifestations arise from a common pathway, resulting in persistent accumulation and activation of CD8⁺ T cells, NK cells, macrophages, and proinflammatory cytokines, resulting in end-organ damage. Adapted with modifications from Paolino et al. [16], with use, distribution, and reproduction permitted under the terms of the Creative Commons Attribution License (CC BY).

Figure 2

Schematic for Recommended Evaluation of Adult HLH. ¹ Though uncommon in adults, central nervous system (CNS) manifestations of HLH are possible and should be evaluated with cerebrospinal fluid (CSF) analysis, as well as magnetic resonance imaging (MRI). ² Given likelihood of malignancy in adults with HLH and its poor prognosis, mHLH must be evaluated promptly. If mHLH is diagnosed, complete cancer workup remains a priority. Biopsy confirmation of malignancy may not be possible in patients critically ill due to HLH; in these cases, we recommend proceeding with HLH-directed therapy, followed by pathologic confirmation when clinically stable. ³ Consider workup of other endemic causes/mimics of HLH (e.g., visceral leishmaniasis, Rickettsia), where appropriate, based on exposures. ⁴ Genetic testing is recommended for suspected primary HLH (young patients or family history) or patients with HLH recurrence, as HLH variants are increasingly recognized with late HLH phenotype emergence [13]. Note: treatment-associated HLH (such as with CAR-T cells or HCT) is considered a separate diagnostic entity and does not require an extensive workup as above due to the temporal proximity of HLH clinical manifestations to the cell therapy administration [49], for which the underlying cause is more obvious.

Figure 3

Treatment schematic of the HLH-94 protocol. * After an 8-week induction, continuation therapy is recommended for all pHLH and persistent or reactivated non-pHLH, which consists of alternating etoposide 150 mg/m² every other week with dexamethasone 10 mg/m²/d for 3 days until HCT. Daily oral cyclosporine A was given in the original HLH-94 protocol during continuation, targeting trough levels of 200 µg/L, though this is often omitted in contemporary regimens. Reproduced with modifications from Henter et al. [53].