A drug currently used to prevent rejection in patients who receive solid organ transplants could have a use in the treatment of a completely different patient population ― those with immune thrombocytopenia (ITP).
The drug is mycophenolate mofetil (MMF) (CellCept), and the new results come from the FLIGHT study from the United Kingdom.
When MMF was used as first-line treatment in combination with steroids, which are the current standard of care of ITP, significantly fewer patients experienced treatment failure in comparison to patients treated with steroids alone.
"The combination of MMF and corticosteroids halved the risk of refractory or relapse ITP," reported principal investigator Charlotte A. Bradbury, MD, PhD, of the Faculty of Translational Health Center at the University of Bristol, Bristol, United Kingdom.
However, the combination was associated with worse patient-reported outcome measures (PROM), such as physical functioning and fatigue, in comparison with steroids alone.
Bradbury was presenting the results at the recent American Society of Hematology (ASH) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.
Mycophenolate mofetil may be considered first-line treatment, along with a short course of steroids, for some patients with ITP, Bradbury commented.
"It may be a good option for patients who are at high bleeding risk and in young patients who are on contraception," she said. One of the benefits of using this drug is that it achieves stable platelet counts in comparison to drugs that are thrombopoietin receptor agonists/mimetics, which are typically given at later relapse, she added.
However, she stopped short of endorsing this approach for all patients. "Most of our patients did quite well," she commented. She noted that more than half (56%) of patients who received steroids in this study did not require second-line treatment.
But she also commented that the response to steroids is heterogeneous. In 30% of patients, disease is refractory, and 70% to 90% of patients experience relapse. "Only 20% of patients show long-term remission on steroids," she said.
"This study is important because many adults with ITP will either not respond to corticosteroids or relapse following a course of corticosteroids," Cindy Neunert, MD, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Irving Medical Center, New York City, told Medscape Medical News. "This study addresses an important gap in knowledge, as it addresses the question of whether the addition of a second agent ― in this case, MMF ― can improve long-term outcomes and prevent those relapse events," she said.
"Overall, the greatest strength of the study is in introducing an up-front regimen that provides more durable responses than standard-of-care corticosteroids," Iberia Romina Sosa, MD, PhD, assistant professor of hematology/oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News.
She added that a second attribute is the emphasis on patient experience data, which shed light on issues that affect compliance with treatment. "A better look at the toxicity profile and patient experience may identify a patient population for whom this regimen is a reasonable first-line therapeutic option," Sosa said.
"Clinical trials are vital for the development and evolution of treatment for hematologic and oncologic disease to provide better outcomes for our patients. This study is important because it raises the question of altering first-line treatment for ITP," Carl Chakmakjian, DO, medical oncologist at Texas Oncology–Waco, in Waco, Texas, told Medscape Medical News.
He also liked the fact that the trial had a straightforward design that was intended to answer a single question. It compared steroids alone vs steroids and MMF in the first-line treatment of ITP.
"Trials designed in this nature provide value to me as a clinician," he said.
He also commented that the question of whether MMF alone would be useful in this patient population is something that could be answered in a future trial.
Clinical Management of ITP
Neunert explained that currently, corticosteroids are the backbone of first-line therapy for ITP. He noted that they provide a "rapid response while waiting for any additive effect of a second agent."
Sosa explained that corticosteroid regimens typically include high-dose, pulsed dexamethasone for one to three cycles or oral prednisone at a dose of 1 mg/kg daily with slow taper. "Overall, pulsed dexamethasone provides a better initial platelet response than oral prednisone, with a reduced toxicity profile," she said.
Updated international guidelines include anti-RhD immunoglobulin (also called anti-D) and intravenous immunoglobulin. Second-line treatment includes rituximab (Rituxan) in preference to splenectomy. TPO mimetics are used in the later stages of treatment.
"MMF is not part of our algorithm, and I would argue that it is rarely used in the US. We may consider it in other scenarios, such as for treatment-refractory ITP or when cost is an issue, as it is cheaper than rituximab or TPO mimetics," she said.
Chakmakjian agreed. "Currently, the use of mycophenolate for ITP is off label in the US. That being said, it is used in clinical practice for refractory cases of ITP," he said. "Mycophenolate is a very cost-effective option for the treatment of ITP, and I suspect this study will generate much discussion and interest," he added.
"The FLIGHT trial definitely provides guidance on the addition of MMF as up-front therapy in combination with corticosteroids," Neunert said. "While the results are promising, more data are likely needed before this is considered a universal approach for all patients," she told Medscape Medical News.
Bradbury noted that in the United Kingdom, MMF has been used as a second-line treatment, but she noted, "The UK is unique in its love for MMF." Retrospective data show high, though delayed, responses with MMF, which is available as a generic and is cheaper than most second-line options, she added.
FLIGHT Study Details
The FLIGHT study randomly assigned patients newly diagnosed with ITP (baseline platelet count: <3 x 109/L) to receive either MMF and corticosteroids (n = 59) or placebo and corticosteroids (n = 62).
MMF was initiated at a dose of 500 mg twice daily. The dose was subsequently increased to 1 g twice daily. After 6 months, the dose was tapered, and MMF treatment was stopped.
"At the end of the study, no patient was receiving MMF," she said. "This was a pragmatic study and allowed clinicians to dose steroids according to their practice," Bradbury noted.
Although the mean age of patients was 54 years, Bradbury pointed out that elderly patients were included in this study; 28% of patients were older than 70, and 16% of patients were older than 75.
The primary endpoint was time to treatment failure (defined as a platelet count <30x109/L and a clinical need for second-line treatment); significantly fewer patients who received the MMF combination experienced treatment failures (22% vs 44% for patients receiving corticosteroids; P = .0064).
Rates of significant adverse events, including infection, neutropenia, and gastrointestinal side effects, were similar between the two groups. Rates of bleeding events, rescue treatments, and hospital admissions were also similar between the groups. However, physical role, physical function, and fatigue ― three aspects of quality of life (QoL) — were worse for patients who received the MMF combination.
Bradbury suggested that the QoL outcomes were related to the older age of many of the trial participants.
Sosa noted that no distinction was made between the type of steroid that was used in the trial but pointed out that pulsed dexamethasone and oral prednisone have different toxicity profiles. "It is unclear if by separating the corticosteroid regimens, the data supporting equivalent tolerability and toxicity of MMF combination vs steroids would be upheld. A subset analysis may help answer this question and shed some clarity into the QoL assessments obtained," Sosa said.
"Patient-reported outcomes obviously need to be looked at more closely but do highlight the need for their comprehensive application in ITP trials," Neunert said. We need randomized trials such as this in ITP that applies relevant PROM beyond just relying on the platelet count as a surrogate marker, she observed.
Bradbury, Neunert, and Sosa have disclosed no relevant financial relationships. Chakmakjian is on the speaker's bureau for Bristol-Myers Squibb.
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