Autoimmune Cytopenias

Presentation and Diagnosis

A 40-year-old male with a past medical history significant for type II diabetes mellitus (T2DM), hyperlipidemia, and untreated HIV presented to the emergency department on 7/18/2021 with a blood glucose level of 463 mg/dL. He reported headaches, dizziness, and diarrhea and had experienced 3 episodes of epistaxis over the 3 days prior. A complete blood count (CBC) was drawn and was significant for thrombocytopenia, with a platelet count of 16,000/µL. (His most recent platelet count had been > 300,000/µL in August 2016.) The patient’s peripheral blood smear showed no evidence of schistocytes or spherocytes. The etiology of thrombocytopenia was thought to be viral-induced (ie, due to untreated HIV).

Initial Treatment
Oral dexamethasone 40 mg daily was initiated for 4 days in addition to antiretroviral therapy with Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide). Four days later, at discharge, the patient’s platelet count had recovered to 107,000/µL. One week after discharge, he followed up with his primary care provider and CBC revealed a platelet count of 15,000/µL. He was treated with prednisone 1 mg/kg (70 mg) by mouth for 14 days with anticipation of a prolonged taper. He was referred to the hematology department for management of chronic immune thrombocytopenia (cITP). After discussion, alternative therapies were considered due to his short-lived response to steroids coupled with persistent hyperglycemia/poorly controlled T2DM. 

Discussion: Alternatives to Treatment With Corticosteroids

After the failure of corticosteroids or intolerance to treatment with corticosteroids, management of cITP becomes more patient-centric, and clinical guidelines do not provide a strong rationale for selection of specific treatments. According to the American Society of Hematology (ASH) 2019 guidelines for ITP, some of the options post corticosteroids include splenectomy, rituximab, fostamatinib, or thrombopoietin (TPO) agonists.¹

Splenectomy. Splenectomy results in a durable remission, defined by the ASH guidelines as a platelet count ≥ 30,000/µL and at least doubling of the baseline count at 6 months, in 50% to 70% of patients with ITP.^1,2 However, this option may not be preferred by patients because it is a surgical intervention. Further, the spleen plays an immunoprotective role in that it contains populations of macrophages that are responsible for attacking encapsulated bacteria. Removal of the spleen results in a deficiency of these macrophages, meaning patients are left at higher risk of infection with encapsulated bacteria such Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.³

Rituximab. Rituximab has also shown significant efficacy in refractory patients, especially when combined with steroids.⁴ Given the current COVID-19 vaccination effort, however, use of this medication requires clinical caution.⁵ Rituximab exerts its effects through depletion of B cells, which are responsible for producing antibodies. When patients are B-cell deficient, they may be unable to mount a strong humoral response to vaccines.⁶

Fostamatinib. Fostamatinib, a novel agent approved for use in cITP, has been shown to generate an overall response rate of 43% but is associated with a median stable response of only 17%.⁷ While there is evidence of higher response rates when fostamatinib is used in earlier lines of therapy, it has not been incorporated into clinical practice as a second-line treatment for cITP.⁸

Thrombopoietin (TPO) receptor agonists. TPO agonists have shown efficacy in the setting of second-line therapy for patients with cITP. Patient responses to romiplostim, for example, can persist for up to 8 years.⁹ TPO agonists bind to and activate the TPO receptor, thereby stimulating the production of platelets. Agents in this class include Nplate (romiplostim), Promacta (eltrombopag), and Doptelet (avatrombopag).

Romiplostim. In a 2010 study, romiplostim was compared with standard-of-care treatment (most often glucocorticoids) to evaluate platelet response, defined as a platelet count > 50,000/µL at any clinic visit. Romiplostim was associated with a 2.3-fold greater platelet response, fewer bleeding events, and a higher quality of life.¹⁰ The most common adverse effects seen with this agent (≥ 5%) include arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia.¹¹ Romiplostim is administered via weekly subcutaneous injections. The FDA label suggests starting patients at 1 µg/kg, but postmarketing studies have demonstrated that starting at higher doses (eg, 3 µg/kg) is safe and provides faster attainment of the goal platelet count.¹² There are no clinically significant drug-drug or drug-food interactions associated with this medication.

Eltrombopag. The EXTEND trial of 2017 examined the safety and efficacy of eltrombopag.¹³ Among 302 patients enrolled, 259 achieved a platelet count greater than 50,000/µL at least once. Further, 52% of patients achieved a response lasting at least 25 weeks. The most common adverse events included hepatobiliary events, cataracts, and deep vein thrombosis. Eltrombopag is administered orally and should be taken on an empty stomach.¹⁴ It should be taken at least 2 hours before or 4 hours after ingestion of antacids or calcium-rich food. The initial dose of eltrombopag is 50 mg daily. The exception is patients with East Asian ancestry or mild to severe hepatic impairment (Child-Pugh classes A, B, or C); for these patients, eltrombopag should be initiated at 25 mg daily. In patients of East Asian ancestry who also have mild to severe hepatic impairment, dosing should be initiated at 12.5-mg daily. If the patient’s platelet count is < 50,000/µL after at least 2 weeks, then the dose should be increased by 25 mg until a maximum dose of 75-mg daily is reached. One study showed that coadministration of eltrombopag and a combination HIV protease inhibitor regimen of lopinavir-ritonavir (Kaletra) resulted in a 17% decrease in the average plasma concentration of eltrombopag AUC.¹⁵ This was attributed to an interaction via the BCRP receptor, of which eltrombopag is an inhibitor and several protease inhibitors are substrates. Platelet counts should be monitored accordingly in patients under treatment with HIV protease inhibitors, such as the patient being discussed in this case study.

Avatrombopag. The Amendment 02 trial conducted in 2018 compared treatment with avatrombopag versus placebo in adults with ITP.¹⁶ Results showed a median of 12.4 weeks of platelet response (≥ 50,000/µL) in patients treated with avatrombopag, and 65.63% of these patients had a platelet response by day 8. The most common adverse events reported with avatrombopag (> 15%) are headache, fatigue, confusion, and upper respiratory tract infection.¹⁷ Avatrombopag is dosed orally and supplied in 20-mg tablets. The initial dose is 20 mg once daily, and platelet counts should be taken once weekly. If a patient’s platelet count does not rise above 50,000/µL after at least 2 weeks of treatment, then the dose should be increased by one “dose level” (see Table 2). If the platelet count is between 200,000/µL and 400,000/µL, then the dose should be decreased by one dose level. Avatrombopag is metabolized by CYP2C9 and CYP3A4. If it is coadministered with moderate or strong dual inhibitors of CYP2C9 and CYP3A4, then the recommended starting dose is 20 mg given 3 times weekly. If it is coadministered with moderate or strong dual inducers of CYP2C9 and CYP3A4, then the recommended starting dose is 40 mg daily.

Summary of the Treatment Decision
TPO agonists have been shown to be safe and effective options for patients with cITP. The patient described in the current case study was treated with avatrombopag. The ability of avatrombopag to quickly increase the platelet count and sustain the platelet response made it an ideal option.

Eltrombopag was considered but was rejected as a treatment option because the patient had also started treatment with Biktarvy;  the tenofovir alafenamide component of Biktarvy is a substrate of BCRP which, as previously mentioned, is inhibited by eltrombopag. Based on its efficacy alone, romiplostim would have been an appropriate option for this patient; however, weekly subcutaneous injections are required. Since the patient said weekly visits to the clinic would be difficult, daily oral dosing of avatrombopag was selected as the better option for him.

The patient’s insurance company posed a barrier to his initiation of treatment with avatrombopag. On 8/12 he had a platelet level of 16,000/µL and received romiplostim at 3 µg/kg while awaiting third-party approval. One week later, his platelet count was up to 26,000/µL, and he received a second dose of romiplostim. Following approval from his insurer, the patient started treatment with avatrombopag at 20 mg PO daily 2 days after his second romiplostim dose. His platelet count increased to 105,000 /µL in just 5 days. Based on this response, the provider decided to decrease his dose to 20 mg PO on Monday, Wednesday, and Friday. This resulted in a platelet count of 64,000/µL at his next clinic visit 1 week later, demonstrating the patient’s response to avatrombopag.

Acknowledgment: This case study was written by Connor Flynn, a PharmD candidate (2022) at Boston Medical Center, and reviewed by David Hughes, PharmD, BCOP.