Mycophenolate reduces treatment failure in immune thrombocytopenia
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The addition of mycophenolate to standard first-line steroid treatment appeared effective for patients with newly diagnosed immune thrombocytopenia, according to study results presented at the virtual ASH Annual Meeting and Exposition.
The regimen — which appeared well-tolerated — reduced by about half the risk for treatment failure, results of the randomized controlled FLIGHT trial showed.
“This is the first randomized trial using mycophenolate to treat immune thrombocytopenia, and it shows we think very good efficacy and surprising tolerability considering the inclusion of many elderly patients ” Charlotte A. Bradbury, MD, MSc, FRCP, FRCPath, PhD, consultant hematologist at University of Bristol in the United Kingdom, said during a presentation. “Mycophenolate may be considered in the first line alongside a short course of corticosteroids for some patients.”
Immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder that results from increased consumption and reduced production of platelets. Patients often experience bleeding and bruising, as well as fatigue and decreased quality of life.
First-line treatment typically consists of high-dose corticosteroids.
“There are several downsides to this approach one being that the majority of patients suffer side effects,” Bradbury said.
One survey showed 98% of patients treated with high-dose corticosteroids experienced at least one adverse event, and 38% stopped treatment or required dose reductions due to intolerable side effects.
Responses to high-dose corticosteroids also are heterogeneous. Only 20% of patients achieve long-term remission. Approximately 30% of patients fail to respond, and the majority of other patients will relapse, Bradbury said.
The immunosuppressive agent mycophenolate often is used as second-line treatment in the U.K. Because it is a generic drug, it is cheaper than many other second-line treatment options, Bradbury said.
Retrospective data suggest 50% to 80% of patients achieve benefit with acceptable tolerability, even though responses often are delayed.
Bradbury and colleagues conducted the multicenter, open-label FLIGHT trial to test the hypothesis that adding mycophenolate to first-line corticosteroid treatment would improve outcomes.
The trial included 120 patients aged older than 16 years (mean age, 54 years; range, 17-87; 52.4% male) with baseline platelet counts less than 30 109/L who required first-line treatment for ITP. More than one-quarter (27.5%) of patients were aged older than 70 years, and 15.8% were aged older than 75 years.
Exclusion criteria included HIV, common variable immunodeficiency, pregnancy, breastfeeding or an unwillingness to adhere to contraception advice if assigned to the experimental regimen.
Researchers randomly assigned 59 patients to corticosteroid treatment plus mycophenolate. The other 61 patients received corticosteroid treatment alone.
Mean baseline platelet count in the cohort was 7 x 109/L, although it was higher among patients assigned the experimental regimen (mean, 7.9 x 109/L vs. 6.5 x 109/L).
Patients assigned mycophenolate were older (mean age, 56.9 years vs. 53.1 years; age 65 years or older, 44.1% vs. 31.2%) and had higher BMI (mean, 29.7 kg/m2 vs. 27.8 kg/m2). Patients assigned corticosteroids only were more likely to be male (60.7% vs. 47.5%), white (96.7% vs. 86.4%) and have secondary ITP (16.4% vs. 5.1%). Treatment groups were balanced with regard to blood pressure, hemoglobin level, total white blood count and neutrophils.
Corticosteroid dosing followed international consensus guidance, with dexamethasone pulses or prednisolone initially dosed at 1 mg/kg daily and then tapered. Mycophenolate dosing followed a taper strategy and was stopped after 6 months.
Time from randomization to treatment failure — defined as platelet level less than 30 x 109/L and clinical need for second-line treatment — served as the primary efficacy outcome.
Secondary outcomes included bleeding events, adverse events and patient-reported outcomes assessed by validated questionnaires at baseline, 2 months, 4 months, 6 months and 1 year.
Mean follow-up was 18 months (range, 12-24).
Results showed a significantly lower treatment failure rate in the mycophenolate group (22% vs. 44%; adjusted HR = 0.41; 95% CI, 0.21-0.8). This finding persisted when investigators excluded patients with secondary ITP (adjusted HR = 0.37; 95% CI, 0.19-0.71).
In addition, a significantly higher percentage of patients assigned mycophenolate achieved partial or complete response to therapy, and fewer mycophenolate-treated patients were refractory to their assigned therapy (6.8% vs. 24.6%).
“Interestingly, at 2 weeks after randomization, the responses were very similar in the two groups,” Bradbury said. “This very much reflects the slower mechanism action of mycophenolate.”
At final follow-up, 56% of patients assigned corticosteroids alone had not required second-line treatment.
“This actually is a really good response and it is higher than previous reports,” Bradbury said.
Fourteen patients in each group developed infections.
A higher percentage of patients assigned mycophenolate experienced difficulty sleeping (35.6% vs. 27.9%) and diarrhea or other gastrointestinal adverse events (33.9% vs. 24.6%), but these differences did not reach statistical significance.
A higher percentage of patients assigned corticosteroid treatment alone experienced weight gain (34.4% vs. 28.8%), developed neutropenia (6.6% vs. 0%), or experienced mood changes or psychiatric disorders (34.4% vs. 30.5%); again, however, the differences did not reach statistical significance.
Two patients assigned corticosteroid treatment only and one patient assigned mycophenolate developed steroid-induced hypertension.
Researchers reported no significant differences between the experimental and standard treatment groups in rates of bleeding episodes (22% vs. 24.6%), blood transfusion (5.1% vs. 1.6%), platelet transfusion (3.4% vs. 0%), receipt of tranexamic acid (8.5% vs. 9.8%), receipt of IV immunoglobulin (13.6% vs. 16.4%) or hospital admission (18.6% vs. 14.8%).
No intracranial hemorrhages or fatal bleeds occurred, and no patients underwent splenectomy during follow-up.
The majority of patients (92.5%) completed quality-of-life questionnaires at a minimum three time points.
Results of the patient-reported outcomes assessment showed some quality-of-life aspects — in the areas of fatigue (P = .05) and physical health (P = .012) — were worse among patients assigned mycophenolate. Results showed no difference in mental health scores between groups.
“It is unclear why some aspects of quality of life seemed a bit worse in the mycophenolate group, and whether that reflects the slightly older age groups included,” Bradbury said. “But it is an important reminder that disease response and patient experience may not absolutely correlate. It also emphasizes the importance of including these types of patient-reported outcome measures within clinical trials.”
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Bradbury CA. Abstract LBA-2. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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