Autoimmune Hemolytic Anemia as a Rare Side Effect of a Therapy with Pembrolizumab for Metastatic Melanoma

Checkpointinhibitors such as pembrolizumab, nivolumab or ipilimumab are indispensable substances in the treatment of advanced or metastatic melanoma. By activation of cytotoxic T-cells they cause an antitumoral response and in many cases a multitude of autoimmune mediated side effects such as colitis, pneumonitis, thyreoiditis or hypophysitis that can usually be recognized quickly. However, there are rare side effects that are not recognized directly because they are not initially interpreted as such. We report the case of a 66-year-old female patient who was diagnosed with a malignant melanoma on her left lower leg in 2015 (nodular melanoma, tumor thickness 3 mm, BRAF, NRAS and c-kit wildtype). Sentinel lymph node biopsy in the ipsilateral groin was positive, a subsequent performed lymphadenectomy showed no further metastases. Six months later she developed lymph nodes metastases in the left groin and several cutaneous metastases on her left leg that could be treated by surgery and an adjuvant radiation (45 Gy). Only a few weeks later she developed a progression of disease with skin and lymph node metastases on her left leg and groin. As a complete surgical removal could not be attained a therapy with pembrolizumab was begun in November 2016. After 12 cycles of this therapy the patient developed of normochromic and normocytic anemia and a drop of haemoglobin (8.4 mg/dl) that needed to be treated with packed red blood cells. Gastric or intestinal bleeding could be ruled out by gastroscopy and coloscopy. A bone marrow biopsy could rule out the infiltration of the bone marrow by melanoma cells as well as a pure red cell anaplasia. Elevated lactatdehydrogenase (LDH) values, decreased values for haptoglobin and reticulocytes in combination with a positive direct Coombs test for c3d an autoimmune hemolytic anemia (AIHA) with involvement of all precursors of the red cell line could be diagnosed. Subsequently, a therapy with methylprednisolone was initiated and led to a rapid improvement of lab values. Each attempt of a re-challenge with pembrolizumab led to a drop of haemoglobin again (6 mg/dl). Therefore, the therapy with pembrolizumab was stopped after 15 cycles, the patient showed no evidence of disease at time of termination. However, some months later the patient showed progression of disease and due to the non-existence of a BRAF-mutation we decided to begin a therapy with nivolumab. The patient did not develop a relapse of her AIHA. The development of an anemia is a rare side effect of therapies with checkpointinhibitors. In these cases either an AIHA or an aplastic anemia may be causative. Up to date there are only a few cases of anemia published that developed under treatment with checkpoint inhibitors. In most cases, anemia developed early after start of therapy and responded only hesitantly to treatment with corticosteroids. According to our knowledge there are only few cases published in which a re-exposure was possible without the development of a new episode of anemia. Some of the cases reported showed a fatal outcome. This elucidates the need of regularly performed lab controls during and even after stop of therapies with checkpointinhibitors. Fortunately, in our case AIHA did not reoccur during treatment with nivolumab. Whether this was due to the fact that pembrolizumab was replaced by nivolumab must currently remain to be unanswered.