Title: HLH after tisagenlecleucel infusion
Submitted by Barbara Dreta, MD, Haematologist, UHC Zagreb, Zagreb, Croatia.
The patient is a 61-year-old female, with no previous medical history. In December 2020. she was diagnosed with marginal zone NHL with large tumor mass and received 6 cycles of BR. Reevaluation confirmed transformation to DLBCL. She received R-CHOP and after disease progression R-GDP and ASCT achieving CR.
In March 2024. the patient relapsed with large intra-abdominal tumor mass and bone marrow infiltration. After bridging with Pola-GDP on 30th April 2024 she received tisagenlecleucel.
On day 2 she developed CRS grade 2 and was treated with tocilizumab. On day 4 despite 3 doses of tocilizumab, fever persisted with no signs of infection so treatment with dexamethasone was started. Her fever resolved completely.
On day 10 she again developed fever this time with pancytopenia, hypofibrinogenemia, hypertriglyceridemia, liver lesion, high ferritin levels (10 000 ng/mL) and high IL-6. Bone marrow showed hemophagocytosis. Microbiology work up turned up negative. She was diagnosed with hemophagocytic lymphohystiocytosis and treated with high dose methylprednisolone (1000 mg for 3 days) and anakinra (100 mg sc BID for 7 days). Steroids were tapered.
Fever resolved and ferritin levels were declining to cca. 2000 ng/ml. The patient was feeling well although cytopenia and hypofibrinogenemia persisted (Plt 30 x109/l, ANC 0.8-1.0 x109/l, fibrinogen 1.0 g/l). After one week malaise, myopathy and worsening of cytopenia occured. MSCT scan confirmed CR, there were no signs of infection. Pancytopenia worsened further (Plt 10 x109/l, ANC 0.5 x109/l) despite daily filgrastim, start of eltrombopag and transfusion support. Ferritin levels increased to 6000 ng/mL with IL-6 in the normal range and no fever. Bone marrow biopsy showed aplastic bone marrow.
Which of the following is the most likely diagnosis?
A. MDS
B. HLH relapse
C. Aplastic anemia
D. Prolonged cytopenia after CAR-T cell infusion
Expert opinion by Barbara Dreta:
Hemophagocytic lymphohistiocytosis (HLH) is a sever hyperinflammation syndrome that manifests itself with fever, hepatosplenomegaly, hyperferritinemia, pancytopenia and coagulopathy. Primary HLH is related to inborn disturbances in immunity. Secondary HLH is a clinical syndrome occurring in patients that do not have inborn defects of lymphocyte cytotoxicity triggered by events such as infection, malignancy, metabolic disorder, rheumatologic disease and specific therapy. CAR-T cell treatment can cause cytokine release syndrome (CRS) that in a subset of patients may manifest itself as HLH. That subset of patients usually develops HLH-like syndrome after CRS is resolved. The risk seems higher in patients with a rapidly proliferating tumor or high tumor burden, an increased baseline inflammation level, immunosuppression, cytopenia and genetic predisposition. The risk seems also higher if certain CAR-T cell constructs and those directed against BCMA are used.
Development of HLH related to CAR-T cell infusion usually starts after resolution of CRS or its initial improvement. Until now, all reported HLH patients had previous or ongoing CRS. Patients develop fever and new onset of cytopenia, hyperferritinemia, coagulopathy with hypofibrinogenemia and/or transaminitis. Laboratory tests show elevated ferritin levels (2x ULN or baseline (at time of infusion) and/or rapidly rising levels), grade 3 hepatic transaminase elevation (>5 x ULN), hypofibrinogenemia, hemophagocytosis in bone marrow or other tissues, and new onset or worsening cytopenia. Patients can also develop LDH elevation, other coagulation abnormalities, new onset splenomegaly, neurotoxicity, pulmonary manifestations and hypertriglyceridemia. It is important to exclude other possible causes of symptoms such as infection and disease progression.
Current treatment approaches are based on HLH-94 and HLH-2004 studies. Their mainstay is treatment with dexamethasone and etoposide and the focus is on life-threatening disease. The patient population developing secondary HLH is heterogenous and includes diverse disease triggers. Corticosteroids are the first line of treatment and are always part of subsequent line therapies. Etoposide with or without corticosteroid has been used for secondary HLH in variable dosage and frequency. Anakinra, the IL-1 antagonist, is most frequently used after initial etoposide treatment. It has an acceptable side effect profile; rapid titration is possible due to a short half-life. Anakinra is the primary treatment of CAR-T cell- related HLH in combination with corticosteroids. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, has been used in small number of studies and reported to have good response ratea in refractory disease. There are several other cytokine-directed therapies such as tocilizumab and empalumab.
This patient developed new onset cytopenia with fever and HLH-like features after initial improvement of CRS symptoms on corticosteroid treatment which is consistent with diagnosis of secondary HLH. She was treated according to EBMT guidelines with anakinra and high dose steroids leading to symptom resolution but with prolonged cytopenia. After steroid tapper the patient’s cytopenia deepened, ferritin levels were rising daily, but without fever.
Considering that the patient was heavily pretreated, development of secondary MDS was a concern, excluded by bone marrow biopsy. Further work up did not reveal any signs of lymphoma relapse or viral infection. Since cytopenia further progressed, ferritin levels were rising and corticosteroid side-effects (steroid-induced myopathy) became significant, further treatment with higher doses of steroids was not plausible. Retreatment with anakinra was carefully considered due to concern of deepening of immunosuppression and high risk of infectious complications in an already immunocompromised patient. Since the cytopenia worsened, treatment with anakinra was initiated in lower dose of 100 mg daily for 7 days with further tapering of steroids. This resulted in recovery of cytopenia. Bone marrow cytology showed no signs of phagocytosis and ferritin levels were slowly declining. After treatment with anakinra was stopped, steroid dose was further slowly reduced with no deepening of cytopenia and recovery of myopathy.
Correct Answer – B
References:
- Hines MR, Knight TE, McNerney KO, et al. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023;29(7):438.e1-438.e16. doi:10.1016/j.jtct.2023.03.006
- Khurana, A., Rosenthal, A.C., Mohty, R. et al. Chimeric antigen receptor T-cell therapy associated hemophagocytic lymphohistiocytosis syndrome: clinical presentation, outcomes, and management. Blood Cancer J. 14, 136 (2024). https://doi.org/10.1038/s41408-024-01119-2
- La Rosée P, Horne A, Hines M, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. 2019;133(23):2465-2477. doi:10.1182/blood.2018894618
- Hayden PJ, Roddie C, Bader P, et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. 2022;33(3):259-275. doi:10.1016/j.annonc.2021.12.003
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