Mycophenolate a Potential First-line Therapy for ITP

Liam Davenport

December 10, 2020

Treatment-naïve immune thrombocytopenia (ITP) patients could more than halve their risk of treatment failure with mycophenolate alongside a course of corticosteroids compared with corticosteroids alone, conclude UK researchers in the first randomised controlled trial of the drug in this patient population.

The research was presented at the virtual 62nd ASH Annual Meeting and Exposition on December 7.


The FLIGHT trial looked at mycophenolate, which is commonly used in the UK as a second-line treatment for ITP, in 120 ITP patients, including many aged over 70 years, randomising them to the drug plus corticosteroids or corticosteroids alone.

Dr Charlotte Bradbury

Presenting the findings Dr Charlotte Bradbury, Faculty of Translational Health Sciences, University of Bristol, Bristol, said the risk of treatment failure was reduced by 59% with the combination versus corticosteroids alone. Dr Bradbury said the drug combination showed "very good efficacy and surprising tolerability considering the inclusion of so many elderly patients" in the study.

With the risk of refractory or relapsed ITP approximately halved, she said mycophenolate "may be considered first-line alongside a short course of corticosteroids for some patients with ITP".

However, there were some signals that, at least in terms of fatigue and overall physical health, quality of life may have been worse with mycophenolate plus corticosteroids.

Dr Bradbury said it is "unclear" why this is the case, adding: "Whether that reflects the slightly older age range recruited, we just don’t know.

"But it is an important reminder that for us clinicians, disease response and patient experience may not absolutely correlate," and the results emphasise the "importance of including these kind of outcomes measures in clinical trials".

In the post-presentation discussion, Dr Bradbury said that they would not advocate the use of mycophenolate for "everyone" in the first line, "partly because over half of the patients who received corticosteroids...didn’t require second-line treatment but also because there’s this signal for, potentially, slightly worse quality of life".

She added that "there may be some patients in whom avoiding refractory or relapsed ITP is really important, either for clinical reasons, such as severe bleeding, or from the patient’s perspective", and so would benefit from receiving mycophenolate.

"Also, if we find predictive biomarkers of corticosteroid response and relapse, potentially we could have more individualised therapy and target mycophenolate to those expected to fail just standard of care."

Rare Condition

Dr Bradbury began her presentation by noting that ITP is a rare condition that "results from increased consumption and reduced production of platelets", resulting in bruising and bleeding, as well as fatigue and impaired quality of life.

The currently recommended first-line treatment is high-dose corticosteroids, "but there are several downsides to this approach," with almost all patients suffering adverse effects and nearly 40% having to stop treatment as a consequence.

"The other big problem is the heterogeneity of responses, with about 30% of patients failing to respond at all," she said, while the majority will relapse "at some point", with only around 20% experiencing long-term remission.

There have been no randomised controlled trials on the use of mycophenolate in ITP, although retrospective data suggests an efficacy of up to 80% and good tolerability, despite responses being "slow", Dr Bradbury said. Moreover, it is a generic drug and cheaper than other second-line options.

The team therefore conducted the multicentre, open-label, randomised controlled FLIGHT trial to examine whether combining mycophenolate with corticosteroids would be more effective as a first-line therapy than corticosteroids alone.

Patients aged over 16 years with a diagnosis of ITP, a platelet count <30x109/L and a clinical need for first-line treatment were recruited and randomised in a 1:1 fashion to corticosteroids or corticosteroids plus mycophenolate (MMFC group).

The corticosteroid could be either dexamethasone or prednisolone, and the dosing followed current consensus guidance. Patients were assessed at 6 months for dose reduction and stopping of mycophenolate "to avoid long-term, unnecessary use," said Dr Bradbury.

Study Details

The team included 120 ITP patients, 54.2% male, with a mean age of 54 years, including 27.5% aged over 70 years and 15.8% over 75 years. The mean baseline platelet count was 7x109/L, and the two groups were well balanced in terms of baseline characteristics.

Over an average follow-up of 18 months, patients in the MMFC group had significantly fewer treatment failures than those given corticosteroids alone, at 22% versus 44%, or an adjusted hazard ratio of 0.41 (p=0.0064).

Dr Bradbury reported that patients given the combination therapy were also more likely to achieve a partial or complete response, "and were less refractory," at only 6.8% versus 24.6% for those given corticosteroids alone (p=0.011).

"Interestingly, 2 weeks after randomisation, responses were very similar in the two groups, and this very much reflects the slower mechanism of action of mycophenolate."

Adverse event rates were similar between the groups, with the most common events corticosteroid-related, such as weight gain, difficulty sleeping, and mood change.

Infection rates and rate of gastrointestinal adverse events were non-significantly different between the groups. However, no patients in the MMFC group developed neutropenia versus four in the corticosteroid-alone group (p=0.12).

Bleeding events, including rescue treatments and hospital admissions, were also non- significantly different between the two patient groups, and there were no intracranial haemorrhages or fatal bleeds.

However, there were marked differences between the MMFC and corticosteroid-alone groups in terms of patient-reported outcomes.

While some broad measures of quality of life were similar, fatigue scores and physical health and mental health summary scores on the SF36 were lower in both groups than the population norm, and notably lower in patients given MMFC than with corticosteroids alone.

While fatigue (p=0.05) and physical health summary scores (p=0.012) were significantly lower with MMFC than corticosteroids alone, none of the differences were significant after Bonferroni correction for multiple testing.


Dr Sioban Keel

In the following discussion, session co-chair Dr Sioban Keel, associate professor of haematology and medicine, University of Washington, Seattle, USA, asked why the study included both dexamethasone and prednisolone when prior studies have shown dexamethasone to be superior in ITP.

Dr Bradbury noted that the randomised trials that have examined the two steroids have indicated that the responses are in fact similar over the long-term, but they may be earlier with dexamethasone, and "both are very acceptable in international consensus guidelines".

Fielding questions from the audience, Dr Keel next asked whether, given what is known about the mechanism of action of mycophenolate, immune cells are affected more than others by the drug.

Dr Bradbury replied that a laboratory sub-study of the trial will be reported separately, which will look at biomarkers of corticosteroid response and the impact on immune cells.

However, she explained that the team did not routinely examine the effect on antiplatelet antibody levels because it is "logistically quite complex", with few centres capable of performing the test, and large volumes of blood required when platelet counts are low.

Dr Christopher Flowers

Session co-chair Dr Christopher Flowers, chair Department of Lymphoma/Myeloma, the University of Texas Anderson Cancer Center, Houston, USA, also asked whether, with additional follow-up on the corticosteroid alone arm, it will be possible to provide data comparing a combination with a sequential approach to treatment.

Dr Bradbury said that many patients in the study did indeed receive second-line mycophenolate but "unfortunately this was a really low budget study, so we aren’t able to collect longer-term follow-up".

Although the question will not be answered by the FLIGHT trial, the team are hoping to "delve" into the UK Adult ITP Registry to examine the efficacy of mycophenolate in the second line.

The study was funded by the National Institute for Health Research under its Research for Patient Benefit Programme

OffLabel Disclosure: Mycophenolate is unlicensed for ITP treatment

No relevant financial relationships declared.

62nd ASH Annual Meeting and Exposition: Abstract LBA-2. Presented 8 December.

Blood 2020; 136 (Supplement_2): LBA-2. doi: 10.1182/blood-2020-143563


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