Refractory Immune Mediated ITP in a Patient with Metastatic Melanoma

Background: Immune check point inhibitors have changed the treatment landscape of many tumors including melanoma. They disrupt the immunoinhibitory signals mediated by programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to use the body's immune system to destroy the tumor. Consequently, they also predispose patients to immune related toxicity which may affect any organ, commonly skin, gastrointestinal, hepatic, pulmonary and endocrine. Hematological immune-related adverse events are less common and include neutropenia, autoimmune hemolytic anemia, immune thrombocytopenia (ITP) and aplastic anemia. Herein we present a case of refractory ITP in a patient receiving immunotherapy for metastatic malignant melanoma.

Case Presentation: A 54-year-old female with metastatic melanoma harboring the BRAF V600E was started on ipilimumab and nivolumab. After 3 cycles of immunotherapy, she was found to have sudden onset thrombocytopenia requiring hospital admission. Complete blood counts showed platelet counts10k/mcL, hemoglobin 13.0 g/dL and white blood cell 4.1 K/uL. She did not manifest any overt bleeding or bruising on history and exam. There was no evidence of hemolysis on labs and peripheral blood smear; thrombotic microangiopathy was ruled out. She received high dose dexamethasone 40 mg intravenous daily and 1 mg/kg intravenous immune globulin daily for three days for suspected ITP due to immunotherapy. Her platelet counts did not improve and therefore a bone marrow biopsy was performed which revealed a normocellular marrow without evidence of melanoma. Imaging revealed excellent radiological response; it was decided to hold further doses of immunotherapy due to severe thrombocytopenia. She received rituximab 375 mg/m ², with no response and platelet counts continued to between 2-5 K/mcL and required daily platelet transfusions. Romiplostim was initiated which improved platelet count to 10K/mcL and she was discharged. The following day her platelet counts dropped to 5K/mcL and she was sent back to the emergency room where she received 1 unit of platelet transfusion. Unfortunately, she developed a cold limb and was found to have a complete occlusion of the right distal popliteal artery and left tibio-peroneal trunk. Initiation of heparin infusion was discussed with the patient, however due to the significant bleeding risk from refractory ITP, the patient decided to pursue comfort measures only and was discharged home for hospice care.

Discussion: About 0.5% of metastatic melanoma patients experience immune thrombocytopenia, deaths caused by this severe adverse event are even rarer. It is postulated that the activation of CD4+ helper T cells and CD8+ cytotoxic T cells can result in the damage to hematopoietic stem cells. Furthermore, nivolumab induced increased production of platelet-specific IgG autoantibodies also promote platelet destruction. Diagnosis is particularly challenging due lack of specific test or markers, and it remains a diagnosis of exclusion. The risk of bleeding, arterial thromboembolism and venous thrombosis is higher in ITP patients. ITP due to immunotherapy may be profound and refractory. One may consider the use of second line agents, such as TPO mimetics earlier in these patients.

Conclusions: Our case highlights refractory ITP as a serious immune related adverse event that failed several lines of treatment strategies. Early diagnosis and combination treatment measures early in the course of the disease is imperative to mitigate associated morbidity and mortality. Combination of steroids immunoglobulins and second line agents may be warranted in some cases, and earlier use of tier 2 agents such as azathioprine should also be considered.