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      Effective Treatment of a Melanoma Patient with Hemophagocytic Lymphohistiocytosis after Nivolumab and Ipilimumab Combined Immunotherapy

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          Abstract

          Immune checkpoint inhibitors have significantly improved the prognosis of melanoma patients. However, these therapies may trigger unexpected immune-related adverse events (irAEs), which are challenging in making the proper diagnosis and providing treatment. Hematological toxicities are possible irAEs, but were poorly evaluated in clinical trials and treatment recommendations of this specific complications are limited. We present a stage IV melanoma patient who developed an extremely rare toxicity – hemophagocytic lymphohistiocytosis (HLH) after the 4 th course of combined immunotherapy with nivolumab and ipilimumab. The patient was steroid resistant and only the treatment with various immunosuppressive agents provided control of the disease and finally melanoma regression. In this report, we evaluated the methods of HLH treatment and described our modification of available protocols. Immediate immunosuppression can be life-saving and due to rarity of this condition as well as lack of specific recommendations, every report is valuable for clinicians, especially when treatment was effective.

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          Most cited references16

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          Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

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            Pembrolizumab versus Ipilimumab in Advanced Melanoma.

            The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).
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              HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.

              In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.
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                Author and article information

                Journal
                PMRRAD
                Prague Medical Report
                Prague Med. Rep.
                Charles University in Prague, Karolinum Press
                1214-6994
                2336-2936
                2022
                2022
                March 6 2022
                : 123
                : 1
                : 35-42
                Article
                10.14712/23362936.2022.4
                35248163
                0caa3a18-efb3-4bdc-ae41-016fe0f1f24e
                © 2022
                History

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