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W. Ghanima et al.
significantly greater improvements, although the magni- tude of the effect was of uncertain clinical benefit.30 In the RAISE study, HRQoL was significantly improved in the eltrombopag arm only, in five of the eight SF-36 domains at week 26 compared to baseline.25 In the EXTEND trial, all the HRQoL instruments used had positive mean changes from baseline over time. The improvements from baseline persisted through five years of treatment.31 This study found positive and clinically-meaningful mean changes from baseline in all HRQoL scores.
Practical issues related to use of thrombopoietin receptor agonists
Indication and dosage
The current label for both TPO-RA in Europe and in the US is patients aged ≥1 year with chronic ITP who are refractory to at least one other treatment (e.g. corticos- teroids, immunoglobulins).
Initial dosing with eltrombopag starts at 50 mg daily, unless the patient is East Asian in whom a lower dose should initially be used. If a response is not seen in two weeks, the dose is increased to 75 mg daily, the maximum dose licensed for ITP. In the RAISE study of 197 adults, approximately equal numbers of patients were on 50 and 75 mg daily after six months of treatment. With romi- plostim, the package insert recommends 1 μg/kg/week and increasing by 1 μg/kg/week until a response is achieved; however, this approach would take nine weeks to achieve the maximum dose of 10 μg/kg/week. A more practical schema would be to start at 3 μg/kg/week, par- ticularly if a rapid response is needed, or one full vial of 250 μg, and increasing weekly to 5, 7, and then 10 μg/kg/week until a response is achieved. Median dose of romiplostim in adults is 3-5 μg/kg/week.27,32 In Europe, approximately one-third of the patients self-administer romiplostim subcutaneously.32 In the US, self-administra- tion is still not licensed; however, this appears likely to be allowed in the near future.
In the pediatric studies, many children needed the max- imum dose of 10 μg/kg/week of romiplostim and 75 mg of eltrombopag, which corresponds to 3-6 mg/kg as com- pared to 0.5-1 mg/kg for adults.23,33-35
Choice of agent
The two TPO-RA have comparable overall efficacy. Eltrombopag is given orally while romiplostim is dosed as a weekly subcutaneous injection. However, eltrombopag must be given on an empty stomach; in particular, it should be taken four hours after and two hours before food con- taining cations, e.g. iron, calcium, milk or other dairy prod- ucts. In the US, different criteria for medical insurance are used for the two agents, which may impact on the decision to adopt one treatment or the other depending on which is likely to be approved first. If patients have absorption problems or transaminitis, it may be prudent to use romi- plostim. If patients do not have stable platelet counts, or if they do not want to come to the clinic every week for injections, then eltrombopag may be better.
Dealing with non-responders: switching or combination
Approximately one-third of the patients discontinue TPO-RA because of lack of response.36 If one TPO-RA does not work, switching to the other TPO-RA has been seen to be surprisingly effective. In a study of 46 patients
who switched from one agent to another, 80% of the patients who failed to respond to eltrombopag eventually responded to romiplostim, and 46% of patients who did not respond to romiplostim responded to eltrombopag.37 These results were confirmed in a more recent retrospec- tive study in which 106 patients underwent switching with 60% achieving response with either agent after switching.38 Switching can also be an effective policy in case of severe platelet-count fluctuations or side-effects.37- 39 Finally, stopping one agent before starting the other is not essential, unless adverse effects are the indication to switch (W Ghanima et al., personal observation, 2019). The addition of a small dose of steroid (2.5-5 mg pred- nisolone) to a TPO-RA may have a good effect in some patients and can be tried in non-responding patients (W Ghanima et al., personal observation, 2019).
Treatment-free durable responses after discontinuation of thrombopoietin receptor agonists
Approximately 10-30% of patients taking a TPO-RA will be able to discontinue their TPO-RA and maintain response after discontinuation.40 In one study of 75 adults with ITP of <6 months duration treated with romiplostim for ≤12 months, 32% were able to discontinue the med- ication and to obtain treatment-free durable responses (platelet counts >50x109/L) lasting at least six months.41 Higher mean platelet count (138x109/L) for the first two months was associated with remission. However, lasting treatment-free response has also been reported in chronic patients. In a retrospective study, 10% of 260 patients treated with eltrombopag maintained acceptable platelet counts after discontinuation of the drug.42 In another small retrospective study of 54 patients who were treated with TPO-RA for at least five years, TPO-RA were discontin- ued in 20 out of 28 patients who achieved a complete response. Of these, eight patients showed a sustained response for a median of 13 months (range 5-27 months).40 However, it is still not known how TPO-RA induce long- lasting off-treatment responses, although it is unlikely that this is simply due to a selection of patients who would eventually remit.41 Durable responses have even been observed in patients with long-lasting disease. Potential mechanisms include: restored immune tolerance by increased exposure to platelet autoantigens, thereby reducing platelet antibodies through increased presence of MK and platelets,41,43 or through improvement of Treg function, which in turn could restore immune tolerance to platelets.13
Predicting who will achieve a durable response and how to discontinue TPO-RA is challenging. We recommend tapering in a patient who achieves and maintains a stable platelet count over 50-100x109/L for at least 3-6 months, particularly if using low doses of a TPO-RA and achieving a normal, stable platelet count for some months. One way to taper treatment would involve gradually decreas- ing and/or increasing the interval between doses until the platelet count remains <30x109/L or it is possible to dis- continue treatment.
Safety and tolerability of thrombopoietin receptor agonists
Ten years after their availability, TPO-RA have been proven to be well-tolerated. The long follow up of the
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haematologica | 2019; 104(6)