A. Diagnostic dilemmas

Daver et al. state that less than 50% of adults with M-HLH received HLH-directed therapy because of lack of awareness and missed diagnosis of this condition in adult patients with malignancies in their center [1]. High morbidity and mortality due to HLH is partially attributed to delay in diagnosis. The rarity of the syndrome, non-specific and overlapping clinical picture with that of infection and sepsis, lack of validated criteria, and scarcity of diagnostic tools such as bone marrow biopsy, mutation testing and molecular assays are among the contributing factors. Online H-Score compiled by Fardet et al. [10] and a list of criteria developed by a panel of experts in the Delphi study [11] are examples of attempts to move towards precision and avoidance of delays in diagnosing HLH.

Our patient presented with fever, upper normal sized spleen, cytopenias affecting RBC and platelets, hypertriglyceridemia, high ferritin, low NK cell activity, thereby fulfilling the diagnostic criteria for HLH (Table 1). This patient was diagnosed with metastatic melanoma 2 years prior to receiving pembrolizumab, therefore it was unlikely that metastatic melanoma itself triggered HLH. In the absence of an infectious cause, we concluded that HLH was related to pembrolizumab.

High fever and hyperferritinemia prompted us to consider HLH in our diagnostic workup. Hyperferritinemia is a non-specific marker indicating inflammatory, infectious, hepatocellular, renal, metabolic and many other processes. However, Carl et al. report that ferritinemia greater than 10,000 μg/L had a sensitivity of 90% and a specificity of 96% for HLH diagnosis [12]. Elevated ferritin levels are also implicated in prognosis. Grangé and colleagues cite that hyperferritinemia greater than 4780 μg/L predicted death with a positive predictive value of 93% but sensitivity of this finding was low (46%) [13].

Our diagnosis was confirmed by immunological studies showing decreased NK cell function and high sCD163 levels. As a hemoglobin-haptoglobin scavenger receptor, sCD163 is a lineage marker indicating macrophage expansion and hyperactivation [5], which may be a useful marker for diagnosis of HLH and related disorders [14]. Soluble IL-2 (also known as sCD25) is a helpful marker for diagnosis and disease severity but not widely available [15].

Bone marrow, lymph node, liver, spleen and even skin biopsies to detect hemophagocytosis and/or lymphocytosis can be used as supportive markers [16]. However, it is well known that the presence of hemophatocytosis or lymphocytosis is neither specific nor sensitive for HLH [1, 16]. Initial biopsy can be negative and repeat biopsies are required for follow up [17]. Daver and colleagues further argue that hemophagocytosis is not pathognomonic for HLH and may cause delayed or missed diagnosis [1]. With sufficient clinical and lab criteria, identifiable cause of HLH, and significant improvement in our patient’s condition, we forewent bone marrow biopsy [18]. However, our conservative approach may not be advisable for most patients unless expert panels identify criteria with defined diagnostic weight and value for M-HLH and other sub-types.

B. Challenges in treatment

Specific HLH treatment guidelines based on randomized trials do not exist [3]. Management of initial phases of genetic and acquired HLH is similar and in addition to supportive therapy, specific treatment is aimed at control of cytotoxicity and immunomodulation. Based on HLH-94 and 2004 protocols, high-dose glucocorticoids, etoposide, methotrexate and cyclosporine are major components of the treatment regimen [19–21]. The efficacy and outcome of these protocols in adults have not been evaluated, although a global analysis of adult case reports indicates that etoposide-containing regimens improve survival in cancer and infection (71–75%) more than in autoimmune diseases (57%) [3]. Patients with genetic HLH may remain on maintenance therapy until allogeneic hematopoietic cell transplantation. In acquired HLH patients, the underlying cause needs to be treated [5]. Additionally, intravenous immunoglobulin therapy (estimated survival rate increase to 59–75%) and plasma exchange (survival of approximately 80%) have been tried. Biological treatments (eg, rituximab, infliximab and etanercept), anti-TNF drugs, anti-interleukin-1r (anakinra), anti-interleukin-6 (tocilizumab), and B-cell depleting drugs (rituximab, belimumab) have shown varying degrees of clinical efficacy in different HLH subtypes [1, 3]. Alemtuzumab, IFN-gamma inhibitor (NI-0501), and Janus kinase 1 (JAK1)/JAK2 inhibitor (ruxolitinib) are novel therapeutic agents either in trials or approved for HLH treatment [1].

The treatment of HLH requires careful analysis of underlying trigger, patient’s performance status, organ functions, and concomitant therapies. In case of M-HLH, the need for such analysis is even more crucial [1]. Treatment guidelines or trials are non-existent for management of M-HLH and HLH as an irAE. A prospective study of 63 patients in China used combination of chemotherapy with liposomal doxorubicin, etoposide and methylprednisolone as a salvage therapy for adult patients with refractory HLH. The regimen resulted in complete remissions in 27% and partial remissions in 49% of the patients [22].

C. HLH due to immunotherapy

HLH has rarely been reported in patients receiving immune checkpoint inhibitors. Shah et al. reported a patient who developed HLH after 9 months of pembrolizumab treated with etoposide and dexamethasone [23]. In contrast, our case was successfully treated with glucocorticoids only suggesting that HLH from immune checkpoint inhibitors may respond to steroids alone.

Satzger et al. reported a 26-year-old female who developed HLH during treatment with nivolumab plus ipilimumab for metastatic melanoma. Their patient was treated with prednisone 2 mg/kg/day, which was tapered to 1 mg/kg/day after a week and mycophenolate mofetil was started 360 mg b.i.d with a subsequent increase to 720 mg b.i.d [24].

Malissen et al. reported 3 cases of “Macrophage Activation Syndrome” (a term traditionally reserved for HLH due to rheumatologic disorders, namely systemic juvenile idiopathic arthritis). The first patient, a 77-year-old male with metastatic melanoma who received Nivolumab therapy, died despite treatment with steroids (0.5 mg/kg). Second melanoma patient, 42-year-old male receiving ipilimumab after initial treatment with nivolumab, recovered with systemic corticotherapy and antibiotics. The third patient, 81-year-old male with Merkel Cell carcinoma developed MAS (HLH) shortly after the first dose of avelumab and died despite high-dose steroids [25].

Takeshita and colleagues reported hemophagocytic syndrome, interstitial pneumonia, and probable Stevens–Johnson syndrome in a 63-year-old woman with stage IV squamous non-small cell lung cancer with nivolumab. Their patient was treated with intravenous methylprednisolone [26], which is comparable to our patient.

T cell–engaging therapies such as the chimeric antigen receptor T (CAR T) cells and bispecific monoclonal antibodies / bi-specific T cell engagers (BiTEs) have been promising in the treatment of highly refractory B cell malignancies [27, 28]. T cell–engaging therapies harness the cell-mediated immune response to attack cancer cells without the involvement of the major histocompatibility complex. The main challenge of T cell-engaging therapies, however, has been toxicity. The most common toxicity is the cytokine release syndrome (CRS), a group of inflammatory symptoms due to cytokine elevations associated with T cell engagement and proliferation. CRS symptoms can range from mild and flulike to a severe inflammatory syndrome, including vascular leak, hypotension, pulmonary edema, and coagulopathy, which could lead to multi-organ failure, similar to HLH and MAS. Steroids and direct targeting of elevated cytokines have shown variable success in the treatment of CRS patients [28].

HLH has also been reported in 2 patients with multiple sclerosis after treatment with alemtuzumab [29], a humanized monoclonal antibody. The first patient, a mid-20s female, died despite treatment with IV corticosteroids and a molecular adsorbent recirculation system procedure. The second patient, a 28-year-old male, was treated with rituximab and corticosteroids.