Ruxolitinib for the treatment of lymphoma-associated hemophagocytic lymphohistiocytosis: A cautionary tale

Abstract

Introduction Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome characterized by fever, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and pancytopenia. Three publications reported success with ruxolitinib, a Janus-associated kinase (JAK1/2) inhibitor. This therapy interrupts the production of cytokines associated with hemophagocytic lymphohistiocytosis, namely interferon-γ and interleukins 2, 6, and 10. Case report We administered ruxolitinib to two patients with lymphoma-associated hemophagocytic lymphohistiocytosis who had failed standard treatment with dexamethasone and etoposide. Management and outcome Patient #1 was started on ruxolitinib 10 mg BID, and titrated to 15 mg BID. All but two of the hemophagocytic lymphohistiocytosis criteria resolved within two weeks, and she was able to restart therapy for lymphoma. During her ruxolitinib taper, she again presented with relapsed hemophagocytic lymphohistiocytosis. She was taking 2.5 mg a day at the time. Despite salvage treatment, she died from the disease. Patient #2 was a diffuse large B-cell lymphoma patient who presented with hemophagocytic lymphohistiocytosis and was treated with chemoimmunotherapy and achieved a complete response (CR). Hemophagocytic lymphohistiocytosis symptoms relapsed, and he was treated with ruxolitinib. He developed relapsed lymphoma and unfortunately died. Discussion While treating the underlying lymphoma is a clear priority, the cytopenias and other symptoms of hemophagocytic lymphohistiocytosis complicate the delivery of this therapy. Hence, the use of ruxolitinib as a bridge to definitive therapy was appealing. However, we are concerned about the progression of lymphoma while these patients were taking ruxolitinib. Ruxolitinib may be controlling cytokine storm associated with hemophagocytic lymphohistiocytosis, while other aspects of the condition are progressing. Therefore, we would advise caution in its use in lymphoma-associated-hemophagocytic lymphohistiocytosis until more data are available.

The role of interferon‐gamma and its signaling pathway in pediatric hematological disorders

“…In this study, all patients experienced at least partial resolution of symptoms and laboratory abnormalities, allowing transfusion independence, discontinuation of glucocorticoid, and hospital discharge. Concern has been expressed, however, about lymphoma progression in patients receiving ruxolitinib for the treatment of refractory lymphoma‐associated HLH 60 …”

COVID-19 as a mediator of interferon deficiency and hyperinflammation: Rationale for the use of JAK1/2 inhibitors in combination with interferon

“…We have severel years’s experience with JAK1/2 inhibitors in the treatment of chronic inflammatory diseases, but also in another acute potentially lethal hyperinflammation syndrome, which is also elicited by virus - the virus-associated HLS [ 4 , [124] , [125] , [126] , [127] , [128] , [129] ]. In this context, preliminary data indicate that the cytokine storm in COVID-19 pneumonia is no exception and may be associated with HLS.…”

“…Unfortunately, this hyperinflammatory syndrome is in several patients characterized by a fulminant and fatal hypercytokinaemia, low blood cell counts due to hemophagocytosis and multiorgan failure. Importantly, as stressed above, ruxolitinib is highly efficacious in HLS and may rescue patients from acute refractory respiratory and multiorgan failure [ [124] , [125] , [126] , [127] , [128] , [129] ]. The efficacy of ruxolitinib in calming the cytokine storm has been thoroughly investigated in animal models of HLS [ [118] , [119] , [120] , [121] , [122] , [123] ], showing that the mechanisms of action involve inhibition of among others CD8 + T cells and important inflammatory cytokines, including IFN gamma [ [148] , [149] , [150] , [151] , [152] ], being of utmost importance for the development of HLS [ 122 , 123 ].…”

“…Murine models of HLS have confirmed the importance of inflammatory cytokines for the development of HLS [ 117 ], and the efficacy of JAK1-2 inhibition for its immediate resolution [ [118] , [119] , [120] , [121] , [122] , [123] ]. Importantly, several clinical studies have shown ruxolitinib to be highly efficacious in HLS [ [124] , [125] , [126] , [127] , [128] , [129] , [130] ], being most recently confirmed in several patients in a single center study [ 129 ]. Of note, in several of these patients, the cytokine storm was refractory to high-dose glucocorticoids [ [124] , [125] , [126] , [127] , [128] , [129] ], which neither previously were WHO recommended for the treatment of the acute respiratory distress syndrome (ARDS) nor imminent multi-organ failure consequent to excessive hyperinflammation in intensive-care patients [ 131 , 132 ].…”

Ruxolitinib Might Be an Effective Hormone Reduction and Replacement Drug in Children With Secondary Hemophagocytic Lymphohistiocytosis 

“…26 Ruxolitinib is a Janusassociated kinase 1/2 (JAK1/2) inhibitor that impedes downstream signaling pathways of cytokines such as interferon-γ, IL-2, and IL-6 to reduce in ammatory responses triggered by these cytokines, which play important roles in HLH. Ruxolitinib was found to control in ammatory storms and prolong survival in secondary HLH model mice; this treatment was effective in 10 cases of HLH, [27][28][29][30][31][32] including one child from abroad. 30 Herein, we present 11 cases of children treated with ruxolitinib.…”