Delayed hemorrhagic gastritis caused by immunotherapy in a patient With metastatic melanoma

Pembrolizumab, nivolumab, atezolizumab, and ipilimumab are therapeutic antibodies that result in an increased activation of the immune system.^,  They are targeted to immune checkpoints, including programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), all of which are negative regulators of T-cell immune function. Nivolumab and pembrolizumab have been FDA-approved to treat metastatic melanoma, metastatic, refractory non-small cell lung cancer, and other advanced cancers. Ipilimumab (CTLA-4 inhibitor) is approved for the treatment of advanced or unresectable melanoma.^,  While checkpoint inhibitors allow for an enhanced immune response toward tumor cells, they can also cause immune-mediated adverse events on normal tissue with the gastrointestinal (GI) tract being the most common organ system.

Common side effects caused by anti-PD-1 therapy include nausea, vomiting, fatigue, and a rash. More serious adverse events include hepatitis, colitis and pneumonitis which can be life threatening. Most adverse events from immunotherapy occur within 3-4 cycles (12 weeks) after initial dose, although there are many documented cases of serious side effects within the first 1-2 cycles after treatment initiation. However, it is possible to have delayed immunotherapy-related adverse events, in fact, one case report showed new-onset colitis after 14 cycles of pembrolizumab in a patient with melanoma. Another case report documented a patient with Hodgkin's lymphoma who started to have diarrhea after receiving 8 cycles (24 weeks) of Nivolumab, and he was found to have histologically proven new-onset esophagitis, gastritis, and colitis. Hemorrhagic gastritis is another very rare, but serious adverse event of PD-1 inhibitors. The first reported case was in 2017, when a patient with metastatic melanoma was found to have hemorrhagic gastritis after 9 cycles of Pembrolizumab. Herein, we reported a case of late histologically proven hemorrhagic gastritis in a patient with metastatic melanoma that occurred after the 23^rd cycle (69 weeks) of pembrolizumab infusion.

The patient was a 52-year-old male with a past medical history of hypertension who was first diagnosed with melanoma of his right great toe in 2008, which was treated with an amputation. He did well until August 2010 when he had local recurrence throughout his right foot for which he required further resection. A PET scan in 2012 demonstrated avid FDG uptake on the right frontal lobe of his brain; he underwent a frontal craniotomy, which confirmed metastatic melanoma. After recovery, he was given 3 cycles of ipilimumab which he tolerated well. He was then monitored for several years until he had a disease recurrence on his right lower extremity in June 2016 with several nodular lesions noted. At that time, his tumor was found to be BRAF WT on biopsy and he was treated with 5 cycles of Pembrolizumab. There was continued progression to his right calf and foot nodes and, therefore, TVEC injections were added to therapy in January 2017. In February 2017, his melanoma continued to progress locally; his current therapy was discontinued, and he was enrolled in a clinical trial of tumor infiltrating lymphocyte (TIL) in May 2017. He did well with his immunotherapy and did not experience any major complications. Three months after his TILs treatment, the patient developed worsening adenopathy of his right lower extremity, so pembrolizumab was re-initiated. He received 23 cycles of pembrolizumab with stable disease on surveillance scans and no significant toxicity. However, nine days after receiving his 23rd cycle, he presented to the hospital with abdominal pain, nausea, vomiting, diarrhea, and dark stools. He had no rash, fever, chills, malaise/fatigue, cough, shortness of breath, dysuria, joint pain, myalgia or jaundice. Physical exam revealed normal body temperature (36.8°C), pulse rate (77 beats/min), blood pressure (100/78 mm Hg), respiration rate (19 breaths/min) and body mass index (24.2 kg/m²). He showed no clinical signs of distress. The abdomen was diffusely tender on palpation, but with no rigidity or guarding. Laboratory tests revealed acute pancytopenia with a low hemoglobin of 8.4 g/dL (a drop from 10 g/dL), low white blood cell count of 2.0 × 10³/µL, and low platelets count of 106 × 10³/µL; normal blood urine nitrogen (BUN) (9 mg/dL) and creatinine (1.01 mg/dL); low albumin at 2.1 g/dL and low total protein at 3.8 g/dL; normal liver enzymes (alanine aminotransferase (ALT) 27 IU/L, aspartate aminotransferase (AST) 24 IU/L and alkaline phosphatase 85 IU/L), and normal total bilirubin at 0.4 mg/dL.

Given his bleeding symptoms, an esophagogastroduodenoscopy (EGD) was performed. It showed diffuse active bleeding with very friable gastric mucosa, consistent with hemorrhagic gastritis (Figure 1). Pathology of gastric biopsies was negative for Heliobacter Pylori (H.Pylori) and cytomegalovirus (CMV), ruling out an infectious cause for the patient's gastritis. Histological features of the gastric biopsy included mononuclear inflammatory cell infiltration in the lamina propria, crypt epithelial lymphocytosis, and neutrophilic infiltration in crypt epithelium, all of which are consistent with hemorrhagic gastritis (Figure 2, Figure 3). Given these findings, it was established that exposure to the PD1 inhibitor was responsible for our patient's condition.

Pembrolizumab was discontinued and the patient was started on pantoprazole twice a day, as well as completing a three-month steroid taper, initiated at 1mg/kg daily. He was not restarted on any immunotherapy and computed tomography scans of chest, abdomen, and pelvis, as well as magnetic resonance imaging of brain showed stable disease. A follow-up EGD three months after discharge showed improvement of gastric mucosa with signs of now chronic gastritis and improved ulceration (Figure 4). Interestingly, the histological features three months later showed a mix of acute and chronic gastritis marked by significantly fewer neutrophils (Figure 5).

PD-1 inhibitors, such as Pembrolizumab, are novel immunotherapies which have proven to be very efficacious in the treatment of advanced cancers including melanoma and non-small cell lung cancer. Immune mediated GI adverse events, including gastritis and colitis, have been a known phenomenon for these agents. The average onset of time of these adverse event ranges anywhere from 1 week to 12 weeks post immunotherapy initiation.

While gastritis and colitis are more commonly seen with immunotherapy, hemorrhagic gastritis is a much rarer event. The first reported case of hemorrhagic gastritis caused by Pembrolizumab in a patient with melanoma occurred after 9 cycles treatment initiation. A literature review revealed that there is only one other reported case of immunotherapy-related hemorrhagic gastritis, which was diagnosed after the 5^th cycle of Nivolumab in a patient with metastatic lung cancer.

Treatment of immunotherapy related adverse events (IRAE) that are grade 2 or higher includes discontinuing immunotherapy and starting systemic steroids. In steroid refractory cases of IRAEs, infliximab is an agent that has shown some benefit in resolving symptoms.^, If IRAE symptoms resolve with treatment, many patients are able to resume immunotherapy. One melanoma patient who developed severe bloody diarrhea after being on Pembrolizumab for 31 weeks had great improvement of symptoms after cessation of immunotherapy and initiation of Infliximab/Remicade; he was ultimately able to resume Pembrolizumab.^, Our patient had quick resolution in bleeding symptoms and maintained a stable hemoglobin while on a prolonged steroid taper. His follow up EGD three months later showed mucosal improvement (Figure 4), but biopsy demonstrated components of both acute and chronic gastritis. While the patient remained asymptomatic after his initial hospitalization, the continued presence of acute on chronic gastritis on biopsy demonstrates the importance of a prolonged steroid taper for patients with immunotherapy-related adverse events. One retrospective study, which analyzed the duration of steroid therapy for IRAEs in 123 patients, showed an average treatment course of 84 days.

Other potential causes of severe hemorrhagic gastritis include pre-existing autoimmune gastritis and medication-related gastritis. The lack of involvement of the esophagus and the histological findings of intestinal metaplasia in our patient helped exclude an autoimmune etiology. While our patient had been on multiple other medications, none were known to cause this pattern of severe gastritis. Additionally, the absence of any evidence of an infectious process causing our patient's condition supports that his case was secondary to immunotherapy.

One part of our patient's history worth noting is his enrollment in the TILs study for refractory melanoma. An abstract from the ASCO 2019 showed preliminary data from the TILs trial in treating metastatic melanoma with an overall response rate of 38%, which makes TIL a promising future therapy for metastatic melanoma. Our patient had tolerated pembrolizumab well prior to undergoing TIL therapy and developed his hemorrhagic gastritis only after restarting pembrolizumab (which he initially tolerated well). As TIL therapy becomes more accepted in the treatment of metastatic melanoma, our case emphasizes the importance of monitoring for symptoms that could be attributed to adverse events from continued immunotherapy after completing TIL therapy.

We report a case of delayed immune-mediated hemorrhagic gastritis secondary to the PD-1 inhibitor, Pembrolizumab. A careful literature review revealed that hemorrhagic gastritis is a very rare adverse event from PD-1 inhibitor treatment. Of the few reported cases, the latest onset of symptoms occurred after the 14^th cycle post PD-1 inhibitor initiation. As cancer patients continue to live longer with immunotherapy, our case demonstrates the importance of awareness of life-threatening adverse events from immunotherapy at any point during a patient's treatment course. These events should be handled by oncology experts with experience in immunotherapy, given the long-term treatment requiring at least several months. Additionally, gastroenterologists should have awareness about these events when evaluating oncology patients.