Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinct subset of cutaneous lymphomas in which neoplastic cytotoxic α/β CD8⁺ T cells infiltrate subcutaneous adipose tissue.^1-3  SPTCL may affect both children and adults.⁴  Systemic symptoms such as fever, asthenia, and weight loss, associated with cytopenias and liver dysfunction, are common. In addition, hemophagocytic lymphohistiocytosis (HLH) is observed in 20% of cases,³  which is associated with poor prognosis and may be the leading cause of death.³  There is no standardized therapy for SPTCL alone or in association with HLH. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone is frequently used, with an overall remission rate of 50%.¹  Immunosuppressive regimens, particularly cyclosporine A (CsA), may be also effective.⁵  In some severe cases, stem cell transplantation has been attempted.¹ 

Recently, germline mutations causing loss of function of T-cell immunoglobulin mucin 3 (TIM-3) were identified in 60% to 85% of SPTCL patients.^6,7  In these patients, TIM-3 deficiency was shown to promote T-lymphocyte and -macrophage activation and the production of proinflammatory cytokines, challenging the malignant nature of skin T-lymphocyte infiltration.⁶ 

Ruxolitinib is a selective JAK1/JAK2 inhibitor licensed for treatment of myelofibrosis and polycythemia vera in adults.^8,9  Studies in animal models of HLH support the efficacy of this drug to prevent and treat HLH in these models.^10,11  Anecdotal experiences of successful use of ruxolitinib to control refractory primary HLH or secondary HLH are also reported in humans.^12-19  JAK1/JAK2 inhibitors are also increasingly used in inflammatory diseases.

We herein report the use and efficacy of ruxolitinib in a patient with recurrence of SPTCL and HLH and in whom TIM-3 deficiency was recently identified.⁶ 

The patient (reported as P4 in Gayden et al⁶  and carrying a homozygous p.Tyr82Cys variant in HAVCR2/TIM-3) is a teenage boy of French Polynesian origin. At 11 years of age, he experienced persistent fever and pain in the right flank. With 5 of 8 positive criteria (persistent fever, pancytopenia, hyperferritinemia [3000 μg/L], hypofibrinogenemia [<0.6 g/L], and hemophagocytosis on bone marrow aspirate), he was diagnosed with HLH.

The patient was treated with corticosteroids, CsA (4-6 mg/kg per day), 4 doses of etoposide (VP16 150 mg/m² per dose), and 1 intrathecal methotrexate injection, which led to complete remission. Corticosteroids were tapered and stopped within 6 weeks. CsA was discontinued after 8 months with complete clinical and biological remission. At 13 years of age, he presented with a relapse of HLH and painful redness of the right flank. A positron emission tomography–computed tomography (PET-CT) scan showed diffuse enhancement of subcutaneous tissues revealing SPTCL, histologically confirmed with monoclonal T-cell receptor β-chain rearrangement of CD8 T cells. CsA was reinitiated (4-6 mg/kg per day), allowing partial remission with intermittent high fever requiring several courses of corticosteroids. Abatacept was added for a period of 6 months without any benefit.

In June 2017, at 16 years of age, the patient’s medical situation became unsatisfactory under CsA treatment (4 mg/kg per day). He had recurrent episodes of fever, persistence of HLH features, lymphopenia, diffuse pain, and persistent mild and diffuse panniculitis with subcutaneous enhancement on PET-CT scan (Figures 1 and 2A). Because the dose of cyclosporine could not be increased due to poor renal tolerance, corticosteroids (0.5 mg/kg per day) were added to alleviate symptoms. One month later, TIM-3 deficiency was identified in this patient, and shown to result in increased in vitro production of tumor necrosis factor-α and interleukin (IL-1β) by the deficient macrophages.⁶  Therefore, the IL-1 inhibitor anakinra (100 mg in daily subcutaneous injection) was initiated, whereas corticosteroids were stopped. This treatment led to overall clinical improvement and prevented fever recurrence⁶  but did not lead to normalization of biologic parameters (Figure 1). Serum levels of interferon-γ (IFN-γ)–induced CXCL10, IL-18, and soluble CD25 (sCD25), a cluster of inflammatory markers characteristic of primary HLH,²⁰  remained elevated (Figure 2B). PET-CT scan performed 6 months after anakinra initiation showed increased diffuse subcutaneous enhancement (Figures 1 and 2A). Of note, CsA was responsible for mild renal impairment but doses could not be tapered because of fever relapse at each attempt.

The research reported in this manuscript has been approved by the local investigational review board and the French Advisory Committee on Medical Research (IRB registration #00001072, no. CPP: 2015-03-03/DC 2014-2272).

Because of the positive IFN-γ signature (discussed in "Case description and methods"), ruxolitinib was initiated (15 mg twice daily/80 kg) allowing rapid improvement of the clinical and biological manifestations of HLH (Figures 1 and 2B). It was possible to taper CsA over 4 weeks and to stop anakinra 2 weeks later without relapse. After 4 months of treatment (including 2 months of ruxolitinib monotherapy), the patient was clinically well and biologically in remission (Figures 1 and 2B). This teenage patient then decided on his own to taper and stop his medication (Figure 1). After 8 months, he came back with fever, marked asthenia, and a large localized panniculitis of his left leg (giant patches of 11 × 13 cm in length) associated with a homolateral enlarged inguinal lymph node (4 × 3 cm). Ruxolitinib discontinuation thus correlated with disease relapse. Clinical manifestations were associated with elevated serum levels of lactate dehydrogenase (LDH), IFN-γ, IL-6, IL-18, CXCL10, and sCD25, whereas lymphocyte counts again decreased (Figure 1 and 2B-C). A large proportion of circulating CD8 T lymphocytes (34.5%) was highly activated in vivo, as assessed by the coexpression of CD38 and HLA-DR molecules at their surface (Figure 2D). A detailed analysis of the circulating T-cell populations over time revealed a CD8 lymphopenia with the presence of a large proportion of effector memory CD8 T cells (CD45RA⁻CCR7⁻) in the patient during flare at the expense of the naive CD8 population (CD45RA⁺CCR7⁺) (Figure 2D). The significant fraction of effector CD8 T cells during flare might reflect a disproportionate T-lymphocyte response to putative infectious trigger occurring in the context of impaired TIM-3 checkpoint inhibition.

Reinitiation of ruxolitinib therapy alone (20 mg twice daily) again resulted in rapid clearance of the fever (within 72 hours) and progressive resolution of the panniculitis within 2 weeks and of HLH features within 3 weeks (Figure 1). The levels of ferritin and inflammatory markers in the serum fully normalized, and lymphocyte counts and distribution reached normal values when analyzed 3 months later (Figures 1 and 2B-D). Ten months later under the same treatment, the patient remained in complete remission of SPTCL (assessed by PET-CT scan) and HLH (Figures 1 and 2A-B). The main adverse events associated with ruxolitinib therapy are hematologic (potential development of cytopenia, anemia, and thrombocytopenia⁸ ) and infectious (shingles and herpes reactivation being the most frequent). In addition, transaminitis was also reported.⁸  No such toxicity events were observed in this patient after 14 months of ruxolitinib treatment. Close monitoring of clinical and biological markers of disease activity will allow ruxolitinib to be tapered to the minimal dose required to maintain long-term remission.

Until recently, the etiology of SPTCL was mostly unknown. The recent description of a genetic defect impairing the function of TIM-3 in a large proportion of SPTCL patients provided some clues to understanding the underlying pathological mechanism of this condition.⁶  TIM-3 acts as a negative immune checkpoint that regulates the effector function of T lymphocytes and myeloid cells.²¹  TIM-3 downregulates the production of proinflammatory cytokines by these cells, which significantly increased levels in SPTCL patients.⁶  Therefore, targeting inflammatory cytokine pathways emerged as a rational therapeutic approach. The clear efficacy of ruxolitinib therapy, both on patient’s HLH and panniculitis manifestations, supports this assumption, although a more extensive clinical trial would be needed to fully validate it. In addition, the efficacy of ruxolitinib therapy in this patient who displayed a severe form of the disease questions the “neoplastic” nature generally attributed to this condition, and invites reconsideration of this entity as an inflammatory condition rather than as a lymphoma.

This work was supported by INSERM, l’Agence Nationale de la Recherche (NewHLH/ANR-18-CE15-0017), La Ligue contre le Cancer (RS19-75-79), and the Histiocytosis Association of America.

Contribution: B.N., F.E.S., and G.d.S.B. conceived and designed the study; F.G., M.F., and A.C. acquired and analyzed data; B.N., R.L., and D.M. evaluated and treated patients; and G.d.S.B., F.E.S., A.F., and B.N. drafted the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Bénédicte Neven, Unité d’Immuno-Hematologie et Rhumatologie, Département de Pédiatrie, AP-HP, Hôpital Necker-Enfants Malades, F-75015 Paris, France; e-mail: benedicte.neven@aphp.fr; and Geneviève de Saint Basile, Imagine Institute, Université de Paris, INSERM U1163, F-75015 Paris, France; e-mail: genevieve.de-saint-basile@inserm.fr.