Immune Checkpoint Inhibitor-Associated Thrombotic Thrombocytopenic Purpura in a Patient With Metastatic Non-Small-Cell Lung Cancer

Abstract

Background: Immune-related adverse events (irAEs) are secondary reactions related to treatment with immune checkpoint inhibitors (ICIs). There have been six cases published reporting on an association between patients undergoing treatment with ICIs and the occurrence of acquired thrombotic thrombocytopenic purpura (TTP).

Case report: We report a 61-year-old male receiving treatment with chemoimmunotherapy followed by pembrolizumab maintenance therapy for advanced non-small-cell lung cancer, presenting with bleeding symptoms, anemia, and thrombocytopenia. The patient received pembrolizumab seven times in total, in three-week cycles. Laboratory testing demonstrated hemolytic anemia, which, in combination with other findings, suggested thrombotic microangiopathy (TMA). PLASMIC scoring and specialized testing with ADAMTS13 activity and inhibitor confirmed a diagnosis of TTP. The patient was started on therapy with plasmapheresis and glucocorticoids, resulting in clinical improvement. The patient chose to leave the hospital under the care of home hospice and died approximately one month after being discharged.

Conclusions: Of the six cases of ICI-induced TTP, only one other was treated with pembrolizumab to our knowledge to date. Our patient experienced an adverse reaction marked by thrombocytopenia and hematuria after drug exposure. With symptom improvement after ICI discontinuation and recurrence on readministration, a presumptive diagnosis of ICI-associated TTP was made. This case report and literature review emphasize the need for close observation of patients undergoing ICI therapy for potential rare irAEs. The further investigation aimed at the study of risk factors, disease severity, and treatment response to this form of secondary TTP is needed to guide treatment decisions.

Keywords: immune checkpoint inhibitors; immune related adverse events; pembrolizumab; thrombotic microangiopathy; thrombotic thrombocytopenic purpura.

Figure 1. Computed tomography of the thorax with contrast at the time of diagnosis with lung cancer

(A) Coronal and (B) axial views demonstrate a large 2.3 × 1.4 cm² nodule in the medial aspect of the left upper lobe suspicious for primary lung cancer (black arrows) with a moderate-sized left pleural effusion and compressive atelectasis in the left lung base.

Figure 2. Computed tomography of the thorax with contrast at the time of lung cancer restaging after induction chemoimmunotherapy

(A) Axial thoracic view demonstrates reduction of the overall disease burden, with the cavitary left apical nodule now decreased in size and lobulated with peripheral cavitary changes, with the solid portion measuring 1.6 × 0.8 cm² (white arrow). (B) Axial abdominal view demonstrates additional satellite nodules have decreased in size, but there is a new 6 mm subpleural pulmonary nodule in the right lower lobe (black arrow).

Figure 3. Magnetic resonance imaging of the thoracic spine at the time of lung cancer progression

Sagittal view demonstrates a mass at T6-7 extending from the medial left rib into the T6 and T7 vertebral body and extending into the spinal canal with contact and displacement of the spinal cord measuring approximately 7 cm × 4.4 cm greatest dimensions in the axial plane and greatest vertical dimension approximately 4.7 cm (white arrow). Anteriorly this lesion abuts the posterior wall of the thoracic aorta.

Figure 4. Peripheral blood smear at the time of presentation with thrombotic thrombocytopenic purpura

Peripheral blood smear revealed near absent platelets, without evidence of clumping, and many schistocytes (black arrows), with >8 per high-powered field.

Figure 5. Computer tomography of the abdomen and pelvis with contrast at the time of presentation with thrombotic thrombocytopenic purpura

(A) Axial upper- and (B) mid-abdominal views demonstrated no evidence of hepatosplenomegaly or retroperitoneal hemorrhage. No evidence of biliary ductal dilatation or focal liver lesions and the portal vein is patent. The spleen, pancreas, and kidneys are normal. There is cholelithiasis without evidence of acute cholecystitis. The bladder demonstrates distention without pelvic mass. There is no evidence of bowel obstruction or pneumoperitoneum. There are no ascites or evidence of retroperitoneal hemorrhage.

Figure 6. Platelet counts from the initial presentation with thrombotic thrombocytopenic purpura

Yellow and orange arrows indicate chemoimmunotherapy cycle start dates. Green arrows represent dates receiving plasmapheresis.

Figure 7. Bilirubin, lactate dehydrogenase, haptoglobin, and reticulocyte count during hospitalization for thrombotic thrombocytopenic purpura

Green arrows represent dates receiving plasmapheresis.

Figure 8. Literature review treatment summary

Literature review summarizing the duration of treatment across five other reported cases of ICI-induced TTP. Cases included in this figure: Youssef et al. [6], Ali et al. [8], Lancelot et al. [9], Dickey et al. [5], De Filippis et al. (current report), King et al. [10], respectively. N.B. The duration of immunotherapy could not be clearly determined definitively in Lancelot et al., but the case was included in this figure to depict the onset of TTP and duration of TPE. LaFranchi et al. were excluded from this figure due to the lack of a clearly defined duration of events. Ali et al. did not have 11 consecutive days of TPE, he was treated for 6 days, platelets recovered so the treatment was paused and 5 days later platelets depleted so he was started on TPE for another 5 days.