Ruxolitinib for refractory large granular lymphocyte leukemia (2021)

Large granular lymphocyte (LGL) leukemia is a T or NK cell clonal disorder characterized by tissue invasion of marrow, spleen, and liver. Clinical presentation is dominated by recurrent infections associated with neutropenia, anemia, splenomegaly and auto-immune diseases, particularly rheumatoid arthritis (RA). It accounts for 2%–5% of chronic lymphoproliferative disorders. Indications for starting therapy are based on occurence of infections related neutropenia, symptomatic or transfusion-dependent anemia or associated autoimmune diseases requiring therapy.1 There is no standard treatment for patients with LGL leukemia. Immunosuppressive therapy remains the foundation of first line treatment including single agents, that is methotrexate, oral cyclophosphamide or cyclosporine (cyclosporin, INN). Usually, refractory patients may be treated with purine analogs, bendamustine or alemtuzumab while polychemotherapy does not provide any good results. There is a clear unmet medical need for such patients whose prognosis is poor. Before moving to targeted therapy, it is important to better understand the pathogenesis of LGL leukemia. Constitutive activation of STAT3 pathway in all LGL leukemia patients has been demonstrated in 2001, while common somatic gain-of-function STAT3 mutations was reported in 28% to 60% of T-LGL leukemia and 30% to 48% of NK LGL lymphocytosis in 2012. Whether or not STAT3 mutation acts as an initial trigger or a late event in LGL leukemia proliferation is still debated. Dysregulations of several signaling pathways including MAPK, PI3K-AKT, NF-ĸB, and JAK/STATs constitute a hallmark of the pathogenesis of LGL leukemia. However, the landscape of mutational events includes also epigenetic and DNA methylation mutated genes.1 We and others have recently reported TET2 mutations in 30% of NK LGL leukemia.2 All these findings open a new window to explore targeted therapy in LGL leukemia. The JAK inhibitors are indeed of potential interest in the treatment of the disease. The JAK3 specific inhibitor tofacitinib has shown clinical efficacy in a series of nine RA patients presenting with refractory T-LGL leukemia.3 Hematologic response was observed in six patients with neutropenia improvement in five patients. One patient experienced an increase of hemoglobin level. The JAK2 inhibitor ruxolitinib is commonly used in myeloproliferative disorders. Interestingly, its effectiveness is not dependent on JAK2V617F mutation status. We therefore evaluated the use of ruxolitinib in two cases of refractory T–LGL leukemia. The initial diagnosis was based on a chronic LGL-T cell expansion (>1 × 109/L) with a typical phenotype (CD3+/CD5dim/CD8+/CD57+) and TCRγ clonal rearrangement. Both patients had a long term medical history of transfusion-dependent anemia and neutropenia, failing or partially responding to immunosuppressive or chemotherapeutic agents. Informed consent was obtained in both cases according to IRB protocol. Case 1: A 36-year-old female was diagnosed with pure red cell aplasia associated to STAT3 mutated T-LGL leukemia. From 2009 to 2017, she successively received high dose immunoglobulin, prednisone, methotrexate, ciclosporin (cyclosporine) and cyclophosphamide leading to transitory and partial remission. In 2018, one course of 2CdA (cladribine) was administered due to recurrence of severe anemia and neutropenia without any hematological improvement. The patient was transfusion dependent and experienced recurrent infections. In July 2019, sixth line therapy with ruxolinitib was then introduced at an oral dose of 15 mg twice per day and resulted in rapid improvement of anemia and neutropenia with complete hematological response. At month 20, patient had hematologic complete response with normalization of blood cell count: Hb 11.3 g/dl, neutrophils 1.78 × 109/L, platelets 335 × 109/L (Figure 1(A)). After 12 months of therapy, bone marrow biopsy evidenced a slight persistence of LGL infiltration (Figure 1(B)). Flow cytometric and molecular analyses showed a drastic and stable reduction of clonal LGL expansion in serial blood samples (Figure 1(C)). At month 20, patient showed a persistent hematologic complete response with normalization of blood cell count: Hb 11.3 g/dl, neutrophils 1.78 × 109/L, platelets 335 × 109/L. Case 2: The second case was related to 70-year-old female with severe pancytopenia and splenomegaly related to STAT3 un-mutated T-LGL leukemia diagnosed in 1990. She failed methotrexate, ciclosporin, cyclophosphamide and 2CdA (cladribine). The patient was transfusion dependent despite 4 months EPO delivery before starting ruxolitinib. In March 2020, ruxolitinib was administered at a dose of 10 mg taken orally twice per day and induced a very good partial remission: the patient became transfusion independent by the third month of therapy. In February 2021, complete blood cell count showed: hemoglobin 10.4 g/dl (EPO not stopped), neutrophils 1.5 × 109/L (G-CSF once a week), Platelets 110 × 109/L. The large spleen was no longer palpable. Both patients did not present any adverse event secondary to ruxolitinib. The JAK inhibitors may be considered as relevant targeting agents for the treatment of cytopenic LGL leukemia patients.4, 5 Different compounds targeting JAK/STAT3 signaling pathway have demonstrated in vitro efficacy on leukemic samples from T-LGL leukemic and aggressive NK cell leukemia patients, depending on the basal activity of mutant STAT3. It has been shown that IL6/IL15 promoted T/NK LGL leukemic expansion through STAT/JAK pathway activation. The ability of STAT3 to promote IL6 gene expression then results in a feed forward autocrine loop. Therefore, we hypothesize that JAK inhibition could induce LGL clone apoptosis through a blockade of a feedback IL6 activation. Clinical efficacy of ruxolitinib was recently reported in a case of refractory severe enterocolitis harboring a STAT3 gene mutation.6 In the two present cases, ruxolitinib was able to induce durable complete and very good partial response (lasting more than 1 year) in two refractory LGL patients. These results make ruxolitinib a potential and promising alternative therapeutic agent in LGL leukemia. This option needs to be further explored in prospective clinical trials. The authors declare no conflict of interest. Data available on request from the authors: The data that support the findings of this study are available from the corresponding author upon reasonable request.