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IL‐1 blockade with anakinra for severe inflammatory symptoms during chemotherapy for acute lymphoblastic leukemia

To the Editor: Anakinra is a recombinant interleukin (IL)-1 receptor antagonist used for several inflammatory conditions including systemic juvenile idiopathic arthritis, recurrent pericarditis, and familial Mediterranean fever (FMF). Its efficacy in blocking IL-1 and its manageable safety profile support its use also in other conditions, such as sepsis, acute myocardial infarction, andCOVID-19.1–4 IL-1 inhibitors, however, have been rarely used in patients with leukemiaor cancer-related inflammatory disorders. We report the use of anakinra therapy for controlling persistent inflammatory symptomsduring chemotherapy for acute lymphoblastic leukemia (ALL). A 17-year-old Iraqi boy with T-cell ALL without cytogenetic abnormalities was treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) BFM ALL 2009 protocol scheme (observational extension), achieving negative (<0.01%) bone marrow minimal residual disease (MRD) by cytofluorometry at the end of the induction phase. During the first high-dose methotrexate course of the consolidation phase, he developed severe renal toxicity; therefore, it was decided to continue treatment using the high-risk consolidation block HR3 from the same protocol, which does not include methotrexate. Ten days after the completion of this course, he was admitted for febrile neutropenia due to an Escherichia coli sepsis. After an initial response to antibiotic therapy, however, spiking fever relapsed, with a marked increase of acute phase reactants and serum ferritin (2077 ng/ml). A full infectiousworkupwas negative, while bone marrow aspirates showed no leukemic blasts but increased histiocytes with signs of hemophagocytosis. The patient did not met all the criteria for hemophagocytic lymphohistiocytosis (HLH)5; however, an inflammatory, noninfectious etiology of the fever was suspected and methylprednisolone was started with complete resolution of symptoms. Perforin, SAP, and XIAP expression in lymphocytes was normal, while natural killer cells showed reduced degranulation after incubation with K562 cells compared to a healthy control (CD107a: 3.3% vs. 11.5%), yet this test was performed while already on corticosteroid therapy. Notably, symptoms recurred at steroid tapering; therefore, it was restarted, again with prompt response. Reinduction phase chemotherapy was then started, with oral dexamethasone in place of methylprednisolone. However, fever relapsed at the scheduled steroid tapering, this time associated with elbows, knees, and ankles joint pain and swelling. Notably, at this time cytarabine therapy of the reinduction had not been administered yet. Involved joints ultrasound showed synovial thickening and fluid effusion. An autoimmune workup was negative. Therapy with dexamethasone was restarted with prompt response, yet fever and joint symptoms relapsed immediately at tapering. The patient also started to present significant adverse effects associated with chronic corticosteroid treatment, especially arterial hypertension and disfiguring severe cutaneous striae. A therapeutic trial of subcutaneous anakinra was started (initially 100 mg once daily, then 100 mg twice daily), with prompt resolution of fever and arthritis and normalization of inflammatory markers, thus allowing steroid discontinuation and chemotherapy resumption (Figure 1). Anakinra was continued also throughout the subsequent chemotherapy courses, without evidence of adverse effects. Cytofluorimetric MRDwas negative, so maintenance therapy with oral mercaptopurine and methotrexate was started, in association with anakinra. Notably, genetic testing revealed a heterozygous missense mutation in the STX11 gene (c.799G>A, p.V267M), associated with familial HLH in homozygous carriers6; and a homozygous E148Q mutation in the MEFV gene, a low-penetrance mutation associated with FMF. After 3 months of maintenance therapy, a combined bone marrow and central nervous system ALL relapse was diagnosed. Secondand thirdline therapy with FLAG-Myocet and the TACL consortium 2005-003 scheme7 was attempted, in association with anakinra, but multiple complications occurred (severe cytopenia, hepatic veno-occlusive disease, sepsis, hemorrhagic cystitis, Cytomegalovirus hepatitis, progressive renal and heart failure), eventually leading to patient demise. Little data are available regarding anakinra therapy in pediatric patients with malignancies and inflammatory symptoms. Demir et al. reported the use of anakinra in association to chemotherapy in a 12year-old girl with FMF and Hodgkin’s lymphoma, without apparent toxicity.8 Our patient presented with persistent inflammatory symptoms complicating and delaying ALL therapy, requiring prolonged corticosteroid treatment. The cause of inflammatory symptoms in our patient is not fully explained. It was not likely associated with ALL, as it was in remission when these symptoms appeared. Clinical presentation was nonspecific and only partly similar to FMF or systemic juvenile idiopathic arthritis. Notably, our patient harbored two genetic mutations (STX11 and MEFV) that may have predisposed him to the occurrence of inflammatory complications. Heterozygous mutations in genes associated with familial HLH like STX11 have been identified in patients with secondary HLH.9–11 FMF is associated with IL-1dependent inflammation, yet the role of hisMEFVmutations is unclear, as he had a low penetrance mutation (E148H), which may be associatedwith no clinicalmanifestations ormild FMFphenotypes. However,