Pembrolizumab-Induced Pancytopenia: A Case Report

Pembrolizumab-Induced Pancytopenia: A Case Report

 

Dinesh Atwal, MD; Krishna P Joshi, MD; Rahul Ravilla, MD; Fade Mahmoud, MD

Perm J 2017;21:17-004 [Full Citation]

https://doi.org/10.7812/TPP/17-004
E-pub: 07/07/2017

ABSTRACT

Introduction: Programmed death receptor-1 blockade with pembrolizumab is approved by the US Food and Drug Administration to treat patients with metastatic melanoma. Activating T cells to fight cancer may cause immune-mediated adverse events. Pembrolizumab-induced pancytopenia has not been previously reported in the medical literature, to our knowledge.
Case Presentation: A 52-year-old Caucasian woman with a diagnosis of metastatic melanoma of the rectum experienced multiple adverse events along her course of therapy with pembrolizumab, ranging from colitis, hepatitis, gastritis, and vitiligo after the fifth cycle of pembrolizumab; to knee synovitis after the 14th cycle; and to severe pancytopenia after the 18th cycle of pembrolizumab. Severe pancytopenia improved after high-dose corticosteroids and a 5-day course of intravenous immunoglobulin therapy.
Discussion: In our case, pembrolizumab-induced Grade 4 pancytopenia resolved via a combination of corticosteroids and intravenous immunoglobulins. Pancytopenia reached a nadir in 10 weeks, and it took 16 weeks for meaningful recovery.

INTRODUCTION

Since the mid-1990s, the medical community has witnessed the birth of immunotherapy to fight cancer. The tremendous discovery of the efficacy of immunotherapy in melanoma paved the way for its application in other types of cancers such as non-small cell lung cancer, head and neck cancers, renal cell carcinoma, and urothelial carcinoma of the bladder.1 The US Food and Drug Administration approved 3 different immunotherapeutic drugs for the treatment of advanced melanoma: ipilimumab, which is a monoclonal antibody against the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and nivolumab and pembrolizumab, which are monoclonal antibodies against the programmed cell death-1 (PD-1) receptor.2,3 These monoclonal antibodies are also referred to as “immune checkpoint inhibitors” because they remove the brakes (the checkpoints) from the immune system and activate T cells.1-3 With activation of the T cells to fight cancer, there is always a chance that these activated T cells might attack normal tissues, leading to immune-related adverse events such as colitis, hepatitis, pneumonitis, endocrinopathies, skin rash, and rarely encephalitis.1-3 Immune-mediated hematologic toxicity could vary from anemia, thrombocytopenia, and leukopenia to rarely pancytopenia (Table 1).4-14 We present the first case, to our knowledge, of pembrolizumab-induced pancytopenia to be reported in the literature.

CASE PRESENTATION

Presenting Concerns

A 52-year-old Caucasian woman presented with episodes of bright red blood per rectum for 1 month. Colonoscopy showed an ulcerated mass in the distal aspect of the rectum. Pathologic analysis confirmed malignant melanoma. The initial positron emission tomography-computed tomography (CT) scan, obtained on October 28, 2014, revealed a rectal mass (3 cm × 2.8 cm × 5.8 cm) along with pelvic and retroperitoneal lymphadenopathy. Figure 1 shows a timeline of the case with relevant history and interventions. Figure 2 shows a timeline of relevant laboratory test results. We received written informed consent from the patient for treatment and inclusion in this case report.

Therapeutic Intervention and Treatment

The patient completed 2 cycles of ipilimumab, 3 mg/kg intravenously every 3 weeks, but severe colitis developed that was resistant to corticosteroids. However, she responded well to infliximab, with a total of 2 doses 4 weeks apart.

Follow-up and Outcomes

A follow-up CT scan of the abdomen and pelvis revealed disease progression, so a regimen of pembrolizumab (2 mg/kg intravenously every 3 weeks) was initiated. After 5 cycles of pembrolizumab, severe gastritis and pancolitis developed, confirmed by biopsy. Clostridium difficile antigen and toxin test results were negative. In addition, the patient developed potentially immune-mediated hepatitis and vitiligo. Pembrolizumab therapy was withheld, and prednisone treatment was initiated at 60 mg/d, with a quick taper in dosage by 10 mg/d every week during the next 4 weeks.

A CT scan of the abdomen and pelvis two months after the fifth cycle of pembrolizumab showed a complete response. Five months after her fifth cycle of pembrolizumab, the patient developed retroperitoneal lymphadenopathy, so pembrolizumab treatment was restarted.

After the 14th cycle of pembrolizumab, low-grade fever developed along with right knee stiffness, swelling, and pain. The patient underwent laparoscopic right knee surgery for repair of a suspected acute medial meniscal tear seen on magnetic resonance imaging; however, during the surgery the synovium was inflamed and was completely excised. Final pathologic results were consistent with acute synovitis, which was believed to be caused by pembrolizumab. The patient responded to a short course of prednisone, 60 mg/d orally, which was used for only 2 days. She refused to continue the medication regimen because of fear of adverse events. Therefore, a single dose of infliximab was given.

Cycle 15 of pembrolizumab was resumed on July 7, 2016, and a month later the patient presented with left knee swelling and pain. She responded well to a course of corticosteroids and resumed pembrolizumab therapy. After Cycle 18 of pembrolizumab, severe pancytopenia developed. Pembrolizumab therapy was again withheld, and the patient received prednisone, 1 mg/kg orally daily, with a tapering dosage over 6 weeks. She continued to have pancytopenia, after which she received a 5-day course of intravenous immunoglobulins (IVIG), 1 g/kg daily. The patient required red blood cell (RBC) and platelet transfusions as well. A bone marrow biopsy specimen was hypocellular for age (20% cellularity).

Results of a repeat bone marrow biopsy 6 weeks after the course of IVIG revealed normocellular bone marrow for age (40% cellularity) with erythroid predominance. Her blood cell counts improved greatly, although remaining lower than normal, and she is doing fairly well at the time of this writing. A repeat positron emission tomography-CT showed complete response.

Pembrolizumab-Induced Pancytopenia: A Case Report

Pembrolizumab-Induced Pancytopenia: A Case Report

 

Pembrolizumab-Induced Pancytopenia: A Case Report

DISCUSSION

Pembrolizumab-induced anemia or thrombocytopenia has rarely been reported. To our knowledge, this is the first case to report the association of pembrolizumab with severe prolonged pancytopenia. In our case, pembrolizumab-induced Grade 4 pancytopenia successfully resolved via a combination of corticosteroids and IVIG. Pretreatment and posttreatment bone marrow biopsy specimens showed that recovery of the peripheral blood cell count lagged behind the bone marrow recovery in our case. A repeated bone marrow biopsy may be considered if pancytopenia does not improve despite treatment with IVIG and a corticosteroid course of 4 to 6 weeks. Le Roy et al4 reported 2 cases of pembrolizumab-induced immune thrombocytopenia that resolved quickly after intravenous methylprednisolone and IVIG. In the KEYNOTE-021 study,5 which is a randomized Phase 2 study of carboplatin and pemetrexed with or without pembrolizumab for treatment of advanced, nonsquamous non-small cell lung cancer, no cases of pancytopenia were reported. However, Grade 3 anemia, neutropenia, and thrombocytopenia were seen in 12%, 3%, and 4% of study subjects, respectively.5 Nair et al6 also reported a case of pembrolizumab-induced autoimmune hemolytic anemia with pure RBC aplasia that was successfully treated with corticosteroids and IVIG.

Few cases of cytopenias have been reported with use of nivolumab. A randomized controlled trial by Weber et al7 described Grade 3 nivolumab-induced anemia in 1% of patients, and this anemia responded well to corticosteroids. Sharma et al8 reported Grade 3 neutropenia in 3% of study subjects and Grades 1 to 2 anemia in 10%, but none of the subjects had Grade 3 or 4 anemia. Evidently, 1 patient experienced Grade 4 thrombocytopenia that resulted in death.8 Schwab et al9 and Kong et al10 each described a case of autoimmune hemolytic anemia associated with nivolumab that responded appropriately to corticosteroids. Inadomi et al11 described a patient in whom bicytopenia developed after nivolumab therapy: Grade 4 anemia and Grade 4 thrombocytopenia. The patient received intravenous methylprednisolone treatment and RBC and platelet transfusions, but his bicytopenia did not recover, and he eventually died.11

Contrary to the anti-PD-1 immunotherapy, pancytopenia has been well documented in association with ipilimumab (anti-CTLA-4 antibody). Di Giacomo et al12 and Zimmer et al13 each described a patient with Grade 4 pancytopenia associated with ipilimumab which resulted in the death of both patients. In addition, du Rusquec et al14 reported a patient with metastatic melanoma who received ipilimumab and subsequently experienced Grade 4 pancytopenia. The patient received high-dose corticosteroids, IVIG, and hematopoietic growth factors and required RBC and platelet transfusions. The blood cell counts improved subsequently, but pancytopenia relapsed a few weeks after another infusion of ipilimumab and required another course of treatment with hematopoietic growth factors and IVIG.14

Immunotherapies are known to cause upregulation and proliferation of T cells and subsequently B cells. During this proliferative response, some of the autoreactive T cells and B cells may go unchecked and subsequently can lead to autoimmune side effects. Our study adds to the growing evidence that immunotherapy can lead to serious hematologic toxicity. Although a few cases of pancytopenia have been described in association with ipilimumab (anti-CTLA-4), none has been reported so far in association with anti-PD-1 inhibitors (nivolumab or pembrolizumab), until this case.

CONCLUSION

With the increased use of immunotherapy in the treatment of metastatic melanoma and other malignancies, physicians are finding themselves in uncharted territory, where we must learn from each other’s experiences. It is extremely important to be familiar with the different immune-mediated adverse events that could occur during immunotherapy and to provide appropriate management. Blood cell counts must be closely monitored, and serious Grade 3 or 4 cytopenias should warrant immediate suspension of the treatment and early intervention with high-dose corticosteroids and IVIG if needed.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Acknowledgements

Kathleen Louden, ELS, of Louden Health Communications provided editorial assistance.

How to Cite this Article

Atwal D, Joshi KP, Ravilla R, Mahmoud F. Pembrolizumab-induced pancytopenia: A case report. Perm J 2017;21:17-004. DOI: https://dx.doi.org/10.7812/TPP/17-004.

References
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