Ruxolitinib Efficacy in a Complex Case of TAFRO-Associated Idiopathic Multicentric Castleman Disease

Abstract

Severe TAFRO-associated idiopathic multicentric Castleman Disease (iMCD-TAFRO) is burdened by adverse prognosis, as systemic inflammation might lead to multi-organ failure and death. Relapsed/refractory cases management remains challenging, as few therapeutic options exist for siltuximab non-responders. Recent findings on JAK-STAT involvement in iMCD-TAFRO pathogenesis promoted JAK inhibitors as a possible new chemo-free salvage option, with very few cases described in literature. We report on a 47-year-old male patient with severe relapsed/refractory iMCD-TAFRO successfully treated with ruxolitinib as salvage therapy in a unique combination setting alongside tocilizumab. Ruxolitinib was effective and excellently well tolerated. More, our case provides insights into new targeted therapy combination strategies in iMCD-TAFRO, suggesting JAK-STAT3 and IL-6 simultaneous blockade might be beneficial. Future studies are needed to determine the role of JAK inhibitors in the treatment of iMCD-TAFRO.

Keywords: Castleman disease; iMCD-TAFRO; Ruxolitinib; JAK inhibitor; Case report.

Introduction

Castleman Disease (CD) delineates a rare group of lymphoproliferative disorders that share specific histopathological features, with a wide range of etiologies and clinical presentations [1]. Thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) syndrome-associated idiopathic multicentric CD (iMCD-TAFRO) describes an aggressive subtype whose clinical course is affected by severe life-threatening cytokine storm, organ failure, and death [2]. Interleukin-6 (IL-6) pathway dysregulation is known to play a crucial role in disease pathogenesis, so that consensus guidelines recommend its blockade using target agent siltuximab as first-line therapy alongside high-dose corticosteroids [3]. However, less than half iMCD and iMCD-TAFRO cases respond to initial treatment, and disease recurrence within 1 to 2 years is quite common [3]. Salvage therapies include immunosuppressive and immunomodulatory agents, while chemotherapy is reserved to specific cases [4]. Despite disease pathogenesis is not yet fully elucidated, recent research identified JAK-STAT3 signaling pathway as strictly connected with mTOR signaling and crucial in iMCD [5]. Based on this rationale, JAK inhibitor ruxolitinib emerged as a new possible therapeutic agent for iMCD-TAFRO, with very few reports described in literature [6-8]. Here we present a case of severe relapsed/ refractory iMCD-TAFRO successfully treated with ruxolitinib in a unique combination setting.

Case Presentation

A 47-year-old male was admitted to the emergency room on November 29th, 2023, due to fever, abdominal pain and severe weight gain (18 kg from baseline of 70 kg) over the previous two weeks. Complete blood count (CBC) revealed severe thrombocytopenia (11 x109/l) and neutropenia (0,45 x109/l), blood tests showed increased ferritin (3540 μg/l), creatinine (2,0 mg/dl), C-reactive protein (32 mg/l, CRP), and procalcitonin (9,5 μg/l, PCT). CT scan revealed hepatosplenomegaly and diffuse serosal effusion. Bone marrow evaluation showed macrophage activation, hemophagocytic focal aspects, dysmegakaryopoiesis, T cell interstitial mild excess, in absence of fibrosis. Patient’s conditions rapidly worsened with acute respiratory failure requiring non-invasive ventilation (NIV) in intensive care unit (ICU). In suspicion of secondary hemophagocytic lymphohistiocytosis in differential diagnosis with adult-onset Still disease, therapy with steroids (dexamethasone 20 mg QD) plus anakinra (100 mg QD) was started on December 1st, 2023 (D1) obtaining a rapid laboratory (platelet count 37 x109/l, creatinine 1,7 mg/dl, PCT 5,4 μg/l), and clinical (4 kg weight loss) improvement within the first 10 days. On D12, a CT-PET scan showed multiple adenopathies (maximal SUV 3.5), and a lymph node biopsy allowed the diagnosis of CD with both hypervascular and plasmacytic features. Diagnostic workup finally led to iMCD-TAFRO diagnosis [2]. During steroid tapering, fever, weight gain, and renal impairment recurred, needing diuretic therapy and the increase of steroids dose, obtaining first complete response (CR1) on D43, assessed via CDCN response criteria [3]. Anakinra was then stopped on D45. Rapidly, the patient experienced another clinical and laboratory relapse (fever, weight gain, CRP, PCT and creatinine increase), therefore conventional therapy with siltuximab plus dexamethasone was started on D75 in association with a short course of anakinra, obtaining second CR (CR2) on D100. On D105 patient experienced a further, more severe clinical (fever, anasarca) and laboratory (platelet count 58 x109/l; creatinine 3,8 mg/dl, CRP 440 mg/l) relapse, that required ICU admission with NIV and continuous veno-venous hemofiltration support. Patient’s critical clinical conditions and severe renal failure hampered a polychemotherapy salvage approach along with immunosuppressive agents more frequently used in severe relapsed cases. Therefore, a single dose (1000 mg) cyclophosphamide was administered on D115, and a long-lasting chemo-free approach was then preferred aiming to disrupt cytokine storm molecular drivers while sparing organ toxicity. Based on this rationale and the few cases reported in literature, ruxolitinib 10 mg BID was introduced on D120 in combination with tocilizumab 8 mg/kg/week, in addition to ongoing dexamethasone and anakinra, used during the acute phase. At the time of ruxolitinib introduction, hemoglobin was 9,0 g/dl, platelet count was 20 x109/l, and leukocytes were normal. After clinical stabilization, tocilizumab was progressively delayed until 8 mg/kg/ month, ruxolitinib was maintained at 10 mg BID, while steroids were tapered without rebound of the symptoms. Clinical course was complicated by probable fungal pneumonia on D145, treated with isavuconazole, a stroke with multiple convulsive events requiring short course ICU on D160, and calcinosis cutis on D185 treated with bisphosphonates. Hemodialysis was stopped on D176, and third CR (CR3) was finally assessed on D194. Ruxolitinib, tocilizumab and low dose prednisone were continued due to clinical benefit and excellent tolerance. Main clinical and laboratory data and treatments from D1 to CR3 are summarized in Figure 1. A CT-PET performed on D280 resulted negative, and after six months of ruxolitinib therapy (D300), ideal body weight (70 kg) was restored, CBC, creatinine, PCT and CRP were normal. At the latest contact (D360), complete response was confirmed.

    

    

    Figure 1: Timeline table displaying clinical and laboratory assessment (upper part) and therapeutic management (lower part) during from D1 to CR3.