Hodgkin’s lymphoma with HLH and complete remission with brentuximab-based therapy

Abstract

A 63-year-old man presented to the hospital with generalised weakness, fatigue and a 22 kg weight loss 4 months after being diagnosed with sarcoidosis on a mediastinal lymph node biopsy, with minimal improvement in symptoms on prednisone and methotrexate therapy. On arrival, he was found to have a haemoglobin of 57 g/L and platelet count of 82×10⁹/L. Further work-up revealed six of eight diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH): fever >38.9°C, splenomegaly, cytopaenia, hypertriglyceridaemia, haemophagocytosis and elevated ferritin >31 000 ng/mL. He was also found to have Epstein-Barr viraemia with greater than 17 000 copies. Bone marrow biopsy showed the presence of haemophagocytic histiocytes and evidence of classic Hodgkin’s lymphoma. He was started on HLH-94 protocol. Later treatment was switched to lymphoma-directed therapy and he finished six cycles of A+AVD (brentuximab vedotin, doxorubicin, vinblastine and dacarbazine) with end-of-treatment positron emission tomography/CT and bone marrow negative for lymphoma.

Background

Haemophagocytic lymphohistiocytosis, or HLH, is a rare but life-threatening syndrome of excess immune activation. The normal downregulation of the immune system by macrophages and lymphocytes mediated through cytotoxic T cells (CTLs) and natural killer (NK) cells is absent, leading to excess cytokine secretion and macrophage activity. This can lead to sepsis, multiorgan damage and death.¹ HLH may occur as a primary or acquired disorder, with the former occurring primarily in children with inherited immune deficiencies.² Acquired, or secondary HLH, is typically seen in adults and commonly associated with malignancy, infection and rheumatological disorders.^{3 4} Principal signs and symptoms of HLH include fever, splenomegaly, cytopaenia, generalised malaise and fatigue.^{2 5} Currently, the diagnosis of HLH is based on the following criteria: molecular identification of an HLH-associated gene mutation or five of the following eight findings: fever, splenomegaly, cytopaenia affecting at least two of three lineages in the peripheral blood, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis in bone marrow, spleen or lymph nodes, low or absent NK cell activity, hyperferritinaemia, and high levels of soluble interleukin-2 receptor (sIL-2r).⁶ Despite these guidelines, confirming the diagnosis of HLH remains difficult as the criteria are non-specific and may be seen in several clinical settings. Once HLH is suspected prompt initiation of treatment is essential; untreated HLH is generally fatal. In a review of 162 patients with HLH, about 20% of patients died in the first month after diagnosis.⁷ Although mortality likely varies depending on the underlying aetiology, a recent study reports an overall mortality of adult HLH as greater than 50%.⁴ Current treatment options include chemotherapy, immunosuppressive and modulatory agents, and haematopoietic stem cell transplantation.³

Prompt recognition of the HLH syndrome along with the underlying specific cause is crucial. Once the underlying cause is identified, early initiation of therapy might control the disease and associated systemic inflammation, leading to improved patient outcomes. Our case is the only second reported case of HLH associated with Hodgkin’s lymphoma achieving a complete remission with brentuximab-based chemotherapy.

Case presentation

A 63-year-old pipefitter presented to the hospital in August 2018 with progressive weakness, fatigue and a 22 kg weight loss. He endorsed a medical history of well-controlled diabetes and hypertension. Four months earlier, he presented to a different hospital with a ‘debilitating’ dry cough and significant fatigue. Work-up included a CT of his chest which demonstrated mediastinal lymphadenopathy without hilar adenopathy or parenchymal abnormalities. He underwent a mediastinoscopy and a lymph node biopsy which led to a diagnosis of sarcoidosis at an outside hospital. He was started on prednisone with brief improvement in his cough and fatigue; however, over the next few months his fatigue progressed. In addition, he was started on weekly oral methotrexate as prednisone was tapered down. He continued to experience progressive weakness and significant weight loss, which prompted him to go to the emergency department for evaluation. On admission, he was found to have bicytopaenia with a haemoglobin of 57 g/L (reference range 130–175 g/L) and a platelet count of 82×10⁹/L (reference range 140–400 ×10⁹/L). On examination he was afebrile and physical exam was only notable for oral thrush.

Investigations

The patient had a repeat CT of the chest, abdomen and pelvis on admission that showed a 1.1 cm supraclavicular lymph node, bulky mediastinal lymph nodes with prevascular lymph nodes of 1.7 cm and 2.5 cm, as well as splenomegaly of 19.5 cm (figures 1 and 2). The pulmonologists consulted because of the recent diagnosis of sarcoidosis were not convinced that he in fact had sarcoidosis given that he lacked hilar lymphadenopathy or parenchymal abnormalities. They recommended obtaining a haematology evaluation for his cytopaenia. On day 2 of his hospitalisation, he developed a fever of 38.9°C and his ferritin came back significantly elevated at 5855 ng/mL (reference range 22–322 ng/mL). Given these clinical manifestations of persistently high fever, cytopaenia, organomegaly and elevated ferritin, the diagnosis of HLH was considered. He had a lipid panel, which showed hypertriglyceridaemia of 417 mg/dL (reference range <150 mg/dL). He met five out of the eight criteria for HLH (based on the HLH-2004 study), including fever, splenomegaly, cytopaenia, hypertriglyceridaemia and elevated ferritin. His calculated HScore came back >260, which predicts a high probability of HLH.

Figure 1.

CT of the chest: cross-sectional image showing bulky mediastinal nodes (1 and 2).

Figure 2.

CT of the chest/abdomen/pelvis: coronal section showing mediastinal adenopathy and splenomegaly.

He subsequently underwent a bone marrow biopsy that revealed a focally fibrotic marrow space with morphological and phenotypic findings diagnostic of classic Hodgkin’s lymphoma. The marrow specimen also revealed increased haemophagocytic histiocytes (figure 3). The lymphoma cells infiltrated 30%–40% of the marrow space, and the Reed-Sternberg cells exhibited immunopositivity for CD30 (membranous and Golgi), dim PAX5 and Epstein-Barr (EBV) virus-encoded RNA (in situ hybridization). Review of his lymph node biopsy (from 4 months earlier) at our institution showed scattered clusters of histiocytic cells without obvious granuloma formation and effacement of nodal architecture by classic Hodgkin’s lymphoma (similar with the bone marrow biopsy) (figure 4). Both the bone marrow and lymph node biopsies had evidence of haemophagocytosis which met six out of the eight HLH criteria. To complete the work-up, a soluble interleukin-2 receptor was evaluated, which was 2395 pg/mL (reference range ≤1033 pg/mL); however, a cut-off of >2400 pg/mL is used in the HLH criteria. His NK cell activity was 7 (reference range was 7–123 LU30). Viral studies demonstrated that he was EBV-positive with 17 168 copies/mL in the whole blood (reference range <200 copies/mL) and were negative for parvovirus B19, HIV and cytomegalovirus. His ferritin also continued to rise from 5855 ng/mL (reference range 22–322 ng/mL) on day 2 to 40 916 ng/mL by day 9.

Figure 3.

Bone marrow core biopsy. H&E stained sections reveal a hypercellular marrow with foci of fibrosis and large atypical lymphoid cells in a mixed inflammatory background (A). These large lymphoma cells stain for CD30 (B) and EBER (C), and reveal dim nuclear PAX5 (D, arrows) consistent with classic Hodgkin’s lymphoma. The marrow aspirate smears (not pictured) revealed an increase in haemophagocytic histiocytes. EBER, Epstein-Barr virus-encoded RNA.

Figure 4.

Lymph node biopsy. Numerous Reed-Sternberg (RS) cells are present in clusters. These RS cells stain strongly for CD30 (A) and demonstrate weak nuclear PAX5 (B, arrows) and absence of CD20 expression (C, arrows) with strong Epstein-Barr virus-encoded RNA immunoreactivity (D).

He was transferred to the inpatient haematology service with a diagnosis of HLH secondary to classic Hodgkin’s lymphoma in the setting of EBV viraemia. He was given a dose of etoposide and Decadron. He had an echo in preparation for treatment of his Hodgkin’s lymphoma as it was driving the severe systemic inflammation. His ejection fraction was normal at 60% and he was initiated on therapy with doxorubicin, vinblastine and dacarbazine. He was discharged 14 days after admission with the plan to continue treatment as an outpatient with the addition of brentuximab.

Three days after discharge he was readmitted for neutropaenic fever found to be secondary to Enterococcus faecium bacteraemia. He was started on vancomycin. On day 3, he developed three episodes of melaena and was transferred to the intensive care unit for an acute gastrointestinal bleeding. He underwent an esophagogastroduodenoscopy which demonstrated a non-bleeding gastric ulcer, which was the likely source of his prior bleeding in the setting of thrombocytopaenia, and was started on a proton pump inhibitor (PPI) without other intervention. His bleeding resolved, and he remained haemodynamically stable and was discharged to complete 14 days of vancomycin for bacteraemia as an outpatient and to follow-up with his haematologist.

Outcome and follow-up

While hospitalised, he was given one dose of etoposide and Decadron for his HLH based on the HLH-94 protocol. His ferritin decreased from over 40 000 ng/mL to under 6000 ng/mL. He received his first cycle of AVD (doxorubicin, vinblastine and dacarbazine) without brentuximab as an inpatient, and 9 months later he has completed six cycles of AVD+brentuximab. EBV level was not detectable in the blood after the first cycle of treatment. He had a positron emission tomography (PET)/CT after cycle 3 of A+AVD (brentuximab vedotin, doxorubicin, vinblastine and dacarbazine) which showed resolution of the lymphadenopathy that was initially seen on CT of the chest, abdomen and pelvis, and his most recent PET/CT after his sixth cycle shows continued complete remission of his disease. He underwent a repeat bone marrow biopsy that showed no morphological evidence of classic Hodgkin’s lymphoma.

Discussion

HLH is a rare but life-threatening syndrome of excess systemic inflammation and immune activation leading to tissue destruction. The normal downregulation of the immune system by macrophages and lymphocytes mediated through CTLs and NK cells is absent, leading to excess cytokine secretion and macrophage activity, which causes tissue damage and can lead to organ failure.⁸ HLH can occur as a familial or sporadic disorder. HLH in adults is often secondary to an underlying condition. It is most commonly caused by viral infection, autoimmune disease or malignancy, and there is often a delay in diagnosis. Prompt recognition so that therapy can be initiated is imperative. In a review of 162 patients with HLH, about 20% died in the first month after diagnosis.¹

Malignancy is a common underlying cause of HLH, and many of these patients will simultaneously have a viral, bacterial or fungal infection that will trigger HLH. This occurs as patients’ immune systems are left dysfunctional from malignancy, and when infected they will have inappropriate cytokine production.⁹ EBV is a common viral trigger of HLH and can also occur in immunocompetent patients.¹⁰ When HLH is associated with a lymphoma, there is considerably higher mortality compared with HLH due to infections and autoimmune causes (overall survival 8% vs 83%, p<0.01).^{5 7}

The most frequently occurring HLH-associated malignancies are T cell or NK cell lymphomas. In these lymphomas, EBV plays an important role in the pathogenesis of haemophagocytic syndrome. Latent membrane protein -1 is considered to induce proinflammatory cytokines leading to the haemophagocytic process. In contrast, HLH is rarely associated with either B cell lymphomas or HL.¹¹ HLH usually co-occurs with Hodgkin’s lymphoma in male patients and predominantly with mixed cellularity and lymphocyte depletion histological types, both of which are strongly associated with EBV.¹²

Establishing a diagnosis of HLH can be challenging. The diagnosis is based on fulfilling five out of eight clinical criteria that were established in 1994 and later updated in 2004. This set of criteria was created based on data for a paediatric patient population and extrapolated to fit the adult population.⁹ Recently Fardet et al ¹³ developed and validated the HScore, which is a scoring system used to estimate an individual’s risk of having a reactive or secondary HLH. This score uses nine variables (three clinical, five biological and one cytological) with a weight assigned to each criterion. This study found that the median HScore was 230 for patients with a positive diagnosis and 125 for those with a negative diagnosis. The probability of having HLH ranges from less than 1% with an HScore of <90 to over 90% for an HScore >250.¹³

Malignancy-associated HLH had the worst prognosis among acquired HLH of various aetiologies.¹⁴ The greatest barrier to treatment and a successful outcome for individuals with HLH is a delay in diagnosis. Once HLH is confirmed, the treatment involves a combination of dexamethasone, etoposide, ciclosporin and intrathecal methotrexate.⁵ In cases of secondary HLH, the literature recommends aggressively treating the underlying process.

For decades, the standard treatment for advanced stage Hodgkin’s lymphoma has been combination chemotherapy.¹⁵ ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy has been the preferred therapy for most patients. Other regimens include Bleomycin, Etoposide, Doxorubicin hydrochloride, Cyclophosphamide, Vincristine, Procarbazine and Prednisone and Stanford V. ABVD is administered every 14 days in 28-day cycles. A+AVD is built on the backbone of ABVD, but bleomycin is replaced by brentuximab vedotin (BV). BV is approved by the US Food and Drug Administration for previously untreated advanced stage classic HL. A+AVD causes less pulmonary toxicity but more peripheral neuropathy and neutropaenia. The ECHELON-1 study was a phase III, open-label, multicentre, randomised study evaluating patients with previously untreated stage III or IV HL assigned to A+AVD and ABVD. At a median follow-up of 24.6 months, the 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% CI 78.8 to 85.0) and 77.2% (95% CI 73.7 to 80.4), respectively, a difference of 4.9 percentage points (HR for an event of progression, death or modified progression, 0.77; 95% CI 0.60 to 0.98; p=0.04).¹⁵ Brentuximab vedotin is an antibody–drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E.

This case illustrates a unique situation in which there was a delay in the diagnosis of Hodgkin’s lymphoma in a patient who developed HLH. Quick recognition of HLH was essential in initiating therapy with etoposide and Decadron. The underlying cause was identified and lymphoma-specific therapy was initiated, leading to improvement in symptoms and definitive treatment of lymphoma. HLH associated with HL is rare. Our patient had a significant delay of 4–5 months in his diagnosis of lymphoma, and by the time it was diagnosed he had developed HLH. EBV was likely an opportunistic infection in the setting of an immunocompromised state from the lymphoma as it quickly resolved after first cycle of chemotherapy was administered. Most of the reported cases of HLH associated with HL were treated with standard ABVD chemotherapy. There is one reported case where BV was used with AVD but only for three cycles due to development of neuropathy.¹² Our patient was started on A+AVD from the beginning and finished all six cycles of therapy. At the time of writing this article, the patient is in complete remission based on PET as well as repeat bone marrow biopsy.

The diagnosis of secondary HLH requires a high index of clinical suspicion. A delay in diagnosis can lead to increased morbidity and mortality for patients. Prompt recognition of the HLH syndrome along with identifying the underlying specific cause is crucial. Once the underlying cause is identified, early initiation of therapy might control the disease and associated systemic inflammation, leading to improved patient outcomes. Fortunately for our patient, despite a delay of 5 months in diagnosis and development of HLH, he still achieved complete remission after appropriate treatment of his underlying Hodgkin’s lymphoma.

Learning points.

• Haemophagocytic lymphohistiocytosis, or HLH, is a rare but life-threatening syndrome of excess immune activation.

• The most common causes of HLH in adults include malignancy, infection or autoimmune conditions.

• Malignancy-associated HLH has a poor prognosis mainly due to a delay in diagnosis and initiation of appropriate therapy.

• Primary signs and symptoms of HLH include fever, splenomegaly, cytopaenia, generalised malaise and fatigue.

• The diagnosis of HLH is based on the following criteria: molecular identification of an HLH-associated gene mutation or five of the following eight findings: fever, splenomegaly, cytopaenia affecting at least two of three lineages in the peripheral blood, hypertriglyceridaemia and/or hypofibrinogenaemia, haemophagocytosis in bone marrow, spleen or lymph nodes, low or absent natural killer cell activity, hyperferritinaemia, and high levels of soluble interleukin-2 receptor (sIL-2r).