Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP)

Background CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. Case presentation We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial. Conclusion The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients.


Background
CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation [1]. Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis [2]. Here, we describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 yearold woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial.

Case presentation
A 68 year old woman with stage III (pT3,N2,M0) ulcerated spindle cell melanoma arising from the anterior aspect of the right inferior turbinate mucosa was referred to our melanoma clinic following definitive surgery. She agreed and signed informed consent for participation in an adjuvant study in which she was randomized to receive ipilimumab, an anti-CTLA-4 antibody, at 10 mg/kg IV every 3 weeks for 4 cycles followed by maintenance therapy.
After the first cycle on 6/29/2015, she developed a grade 1 pruritic rash and grade 1 ALT and AST elevation. She received cycle 2 on July 20, 2015. Prior to receiving cycle 3, transaminases increased further to grade 2. As a result, cycle 3 was held and the patient was started on prednisone 40 mg daily, and then tapered over 4 weeks to 5 mg prednisone daily. The transaminase elevation decreased from grade 2 to grade 1 and cycle 3 was given on 8/24/15. During that time, she was found to have an otitis externa and was prescribed topical ciprofloxacin + dexamethasone drops from 8/24/2015 to 9/ 10/2015, followed by oral clindamycin 300 mg TID from 9/1/2015 to 9/11/2015. When seen on 9/9/2015, she had grade 1 transaminase elevation, mild hyperglycemia, normal renal function and a very mild microcytic anemia. Platelet count and leukocyte count were normal.
On September 12, 2015, the patient developed profound fatigue, decreased PO intake, nausea, vomiting, and two episodes of diarrheal stools. She presented to clinic on September 14, 2015. On the morning of her evaluation, she complained of subjective fevers, altered mental status, and worsening fatigue. Physical examination was remarkable for a petechial rash over the chest and bilateral upper extremities. Laboratory evaluation demonstrated a severe microcytic anemia and thrombocytopenia, with a hemoglobin of 6.8 g.dL and a platelet count of 7,000/uL. There was mild leukocytosis with a WBC of 12,700/uL. Examination of the peripheral blood smear (Fig. 1) showed marked anisocytosis, severe decrease in platelets and the presence of abundant schistocytes. Reticulocyte count was 5.41% (ULN 2.1%), serum LDH was 7,329 (ULN 618 U/L) and serum haptoglobin was < 7.8 mg/dL (LLN 30 mg/dL). Acute renal failure was characterized by oliguria, serum creatinine of 2.8 mg/dL and BUN 98 mg/dL. Serum transaminases were mildly elevated. Serum bilirubin was 2.1 mg/dL (ULN 1.3 mg/dL). Sedimentation rate was 75 mm/h (ULN 30 mm/h) and serum C-reactive protein was 18.7 mg/L (ULN 3 mg/L). Blood cultures and disseminated intravascular coagulation panel were negative. ADAMTS13 activity and inhibitor level were collected upon admission to the hospital.
She improved clinically over the next several days with reversal of renal failure, increased hemoglobin and haptoglobin, normalization of LDH, and no recurrence of mental status changes. By September 23, 2015, LDH, haptoglobin, renal function, and platelet count were normalized. She was given rituximab on 9/24/15 and discharged home. Results of ADAMTS13, available on day 7, revealed that ADAMTS13 activity was <3% (normal: 68-163% activity); ADAMTS13 inhibitor was 3.7H (normal: <0.4 BEU).
Follow-up as an outpatient has shown no evidence of TTP recurrence to the date of this report. She was permanently taken off ipilimumab and remains under close monitoring for her high-risk melanoma.

Discussion
TTP is a primary thrombotic microangiopathy manifested by consumptive thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and thrombosis. The underlying pathophysiology of TTP is inhibition/inactivation of A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats, 13 (ADAMTS13), a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating large multimers of vWF promotes platelet adhesion to areas of endothelial injury, particularly at arteriole-capillary junctions. As a consequence, passing red blood cells are subjected to shear stress leading to rupture of red blood cells within blood vessels, producing hemolytic anemia and schistocyte formation. Reduced blood flow due to thrombosis and cellular injury, results in endorgan damage.
Many patients also present with neurological symptoms, renal involvement, and fever [3,4]. The classic pentad of microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, renal failure, and fever, albeit uncommon, has been traditionally considered to be diagnostic of the disease.
While most cases of TTP are caused by ADAMTS13 autoantibodies, secondary TTP can also be caused by drugs, bone marrow transplantation, and HIV infection. TTP may occur due to a congenital deficiency of ADAMTS13 (Upshaw-Shulman syndrome) in about 1% of patients.
Here, we describe the first report, to our knowledge, of TTP associated with the use of ipilimumab. Although it is possible that this patient could have had secondary TTP from oral clindamycin therapy, a literature search failed to demonstrate clindamycin-induced TTP. There have been 2 cases reported of clarithromycin-induced TTP [12]. Ciprofloxacin has been associated with TTP but our patient was treated with topical ciprofloxacin drops only [13].
Although rare, there have been reports of isolated hemolytic anemia and thrombocytopenia related to Ipilimumab therapy [14]. Given the wide variety of immune manifestations reported with the use of ipilimumab and the autoimmune underlying nature of TTP, TTP should be added to the list of possible immune-related adverse events of ipilimumab and considered in the differential diagnosis of ipilimumab-associated thrombocytopenia.

Conclusion
With the advent of immunotherapy as a dominant modality in cancer treatment, it is essential for clinicians to be able to quickly identify and treat the common associated and rare immune related toxicities. This requires a high degree of clinical suspicion when addressing patient reported signs and symptoms.