Eltrombopag therapy in newly diagnosed steroid non-responsive ITP patients
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- Tripathi, A.K., Shukla, A., Mishra, S. et al. Int J Hematol (2014) 99: 413. doi:10.1007/s12185-014-1533-y
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Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterised by isolated thrombocytopenia (peripheral blood platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia. The upfront treatment in newly diagnosed ITP patients is steroids; however, about one-third patients do not respond, and require other treatment, including IVIg, anti-D, or splenectomy. Previous studies have shown decreased platelet production in some ITP patients, aside from the evidence of enhanced platelet destruction. Thrombopoietin receptor agonists (TPO-RA), such as eltrombopag have been shown to provide good response in steroid non-responsive chronic ITP patients. We have studied response to eltrombopag in 25 newly diagnosed steroid non-responsive ITP patients; 80 % patients showed response at the end of 1 month, and 76 % sustained response at the end of 3 months. The platelet count rose from a mean value of 17.5 ± 3.6–152.5 ± 107.9 × 109/L at the end of 1 month. Our results suggest a possible role of eltrombopag in newly diagnosed steroid non-responsive ITP patients. However, our study is limited in that it is a single-centre study, with a small sample size, and lacks a long-term safety profile. Our findings highlight the potential value of a larger prospective study on the upfront use of TPO-RA in patients of ITP.
Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterised by isolated thrombocytopenia (peripheral blood platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia . The diagnosis of ITP remains one of exclusion; no robust clinical or laboratory parameters are currently available to establish its diagnosis with accuracy. The main clinical problem of ITP is an increased risk of bleeding, although bleeding symptoms may not always be present. ITP is said to be “newly diagnosed” if time of presentation from the diagnosis is within 3 months and chronic if lasting for more than 12 months .
The disease is characterised by enhanced destruction of antibody-coated platelets in the reticuloendothelial system. In some patients, there is also an evidence of immune-mediated megakaryocytic suppression/injury . The main aim of the treatment is to avoid bleeding by augmenting the low platelet counts that may have caused bleeding.
As there is no consensus for etiology, similar is the situation with treatment. Treatment strategies have focussed on limiting the accelerated platelet destruction. Steroid is the initial treatment choice but 1/3 patients do not respond or need intolerable, larger doses . The mechanism by which steroid acts is not very clear, however, it is supposed to be through its immunosuppressant effect on T cells. In patients not responding to steroids, various treatment options are splenectomy, anti-D, IV immunoglobulin, Rituximab, danazol, vincristine, etc. .
Thrombopoietin receptor agonists (TPO-RA: oral eltrombopag, subcutaneous romiplostim) have been tried in patients with ITP on the basis that there is megakaryocytic suppression/injury in some, if not all, patients of ITP. Previous studies have shown that eltrombopag increases the platelet counts significantly in patients of chronic ITP and reduces the morbidity and mortality associated with the disease . These studies have focussed on the role of TPO-RA in patients of chronic ITP who failed steroid therapy or other first-line treatment. However, there is a paucity of published research work on the role of TPO-RA in newly diagnosed (time of diagnosis within 3 months) ITP patients who have failed steroid therapy. We hereby prospectively studied the response to eltrombopag in newly diagnosed ITP patients non-responsive to steroid and sought to know the durability of response on TPO-RA.
This prospective cohort study comprised 27 patients of primary ITP from the hematology clinic who fulfilled the inclusion criteria such as:
1. “Newly diagnosed ITP” (time from diagnosis within 3 months).
2. Non-responsive to steroid at 2 weeks.
3. Could not opt for IVIg, anti-D or splenectomy as further treatment.
The study was approved by the institutional ethical committee and all patients had given a written informed consent before enrolment. Non-responsiveness to steroid was defined according to international working group consensus .
Cases of ITP associated with secondary causes like HIV, SLE, H. pylori, other cancer and pregnancy were excluded from the study.
Cases underwent detailed clinical history, physical examination and investigations. A complete hemogram with thorough peripheral blood smear examination and tests to exclude secondary causes of ITP including viral profile (HIV, HBsAg, HCV), H. pylori, anti-thyroid, and ANA and APLA were done.
Patients of newly diagnosed ITP who did not respond to steroid therapy were given eltrombopag. Initial dose was 50 mg/day for 1 month which was tapered to 25 mg/day if platelet count was sustained >150 × 109/L for a week. Steroid was tapered in 2 weeks after eltrombopag was started. Platelet count was done biweekly for first month, and then monthly for 3 months. Decision to stop therapy was taken if counts rose above 250 × 109/L in order to reduce the thrombocytosis-associated risk. If there was no response at 1 month or anytime later, patients were offered choice of other modalities like splenectomy, anti-CD 20, etc.
The primary end point was defined as a response to eltrombopag that is platelet count more than 50 × 109/L at the end of 1 and 3 months of treatment. The secondary end points included safety and tolerability, affordability and signs of bleeding. The incidence and severity of bleeding were assessed at every visit according to WHO bleeding scale.
The patients were followed fortnightly. The clinical course including symptoms and side effects was recorded on a regular follow-up.
Out of newly diagnosed ITP patients (time from diagnosis within 3 months) attending OPD/IPD clinics, only those (n = 27) patients were included in the present study who did not respond to steroid. Two patients were lost during follow-up and there results are not included. The mean age of patients (n = 25) was 27 ± 8.63 years. All patients were 15 years old or above (range 15–55 years). Males constituted 40 % (10/25) of the study population. The mean platelet count at presentation was 13.7 ± 5.2 × 109/L, median 12 × 109/L and the range was 20 × 109/L. Clinical features included petechiae and purpura in 68 %, ecchymosis in 40 % and mucosal bleeding in 60 % of patients. All patients were newly diagnosed (time from diagnosis within 3 months) cases of primary ITP and were treatment-naive. All patients were treated in outpatient clinic or day care centre. Indications for treatment were bleeding in 76 %, platelet count ≤10 × 109/L in 8 %, and both features in 16 %.
Patients who were included in the study had already received prednisolone at a dose of 2 mg/kg/day for 2 weeks did not show response nor chose to go for splenectomy or other therapy such as IVIg or anti-D. The mean platelet count in these patients at the end of 2 weeks of steroid treatment was 17.5 ± 3.6 × 109/L, median 18 × 109/L and the range was 16 × 109/L. These patients were given 50 mg/day of eltrombopag, and steroid was gradually tapered and discontinued within 2 weeks.
Five patients who did not respond to eltrombopag 50 mg and one patient who lost response subsequently were offered other options along with splenectomy.
No significant difference in response to eltrombopag between male and female population was noted. Two patients had platelet count of more than 200 × 10−9 but did not withdraw from the study.
Bleeding episodes and severity decreased significantly in all those who achieved response (76 %). Bleeding symptoms were assessed by the WHO scale.
Six of our patients (24 %) had mild headache on eltrombopag treatment but did not necessitate any treatment. No patient was reported with episode of thrombosis. Three of our 25 patients (12 %) had mild elevation in ALT (<60 IU) and hence did not require any intervention. The values returned to normal within 1 month.
ITP is characterised by isolated thrombocytopenia (peripheral blood platelet count <100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia . The upfront choice of therapy is steroid. Various studies in past have reported response to steroid in 53–80 % patients . Patients who do not respond to steroid are given additional therapy like IVIg or anti-D and those who are non-responsive are candidates for splenectomy. The manner in which steroid acts is not adequately known; however, it is thought to be by suppression of T cell and antibody-mediated destruction of platelets . Why one-third patients of ITP do not respond to steroid is not precisely known. It may be assumed that these patients may have other prominent pathogenic mechanisms for thrombocytopenia in addition to increased platelet destruction [5–9].
Houwerzijl et al.  have reported evidence of megakaryocytic suppression or injury contributing to thrombocytopenia in patients of ITP. This has formed the basis for the use of newer agents that accelerate production of platelets. TPO-RA such as eltrombopag and romiplostim have been tried in patients with chronic ITP and phase II/III trials have shown a good response with adequate safety and efficacy [10–12]. Conventionally, in the steroid non-responsive newly diagnosed patients, the choice is IVIg or splenectomy. In our setup, most patients are either not able to afford IVIg (average cost of therapy being $2500) or are not willing to undergo splenectomy due to culturally inherent fear of surgery. Also splenectomy has its own limitations. It is effective only in 60–75 % of patients and is associated with an increase in the risk to thrombosis. Hence splenectomy in newly diagnosed ITP may be a hasty decision. Moreover, few patients of adult ITP may attain spontaneous remission once the effects of severe or symptomatic thrombocytopenia are taken care of and splenectomy can be avoided in them . Eltrombopag has previously been used effectively in chronic ITP patients who were non-responsive to steroid or other agents [4, 10, 11]. However, its role in newly diagnosed ITP patients is yet undefined. There is need for newer agents to be used in newly diagnosed ITP patients who do not respond to steroids. These agents should be able to increase the platelet count within days in order to cover the period of bleeding or severe thrombocytopenia. This justifies the use of TPO-RA in newly diagnosed ITP patients. According to current practice guideline, TPO-RA is not initial treatment of choice in either naive, newly diagnosed patients or patients non-responsive to steroid. Safety of TPO-RA in its short term and to some extent long term uses is now established by various studies. In addition, the response to eltrombopag is visible within few days and the response is durable. Hence, we sought to explore the role of eltrombopag in newly diagnosed ITP patients (diagnosed within 3 months) who were non-responsive to steroid. We used eltrombopag as it has convenient oral dosing and is easily available.
Effect of initial platelet count on response to treatment with eltrombopag
Initial platelet count
No. of patients
At 1 month treatment
At 3 months treatment
189000.00 ± 144391.10
133666.70 ± 74395.34
141052.60 ± 95715.71
105736.80 ± 63978.16
We tapered the dose of eltrombopag to 25 mg daily in the responders and offered other options as splenectomy to the non-responders. At the end of 3 months, response was seen to be persisting in 76 % patients, which was higher than the response seen in patients of chronic ITP as studied by Cheng and Saleh [10, 11]. So the response to eltrombopag in newly diagnosed patients can be considered to be more durable than in patients of chronic ITP.
The mechanism by which TPO-RA increases platelet count in patients not responding to steroid is a matter of further studies. However, it is likely to be due to stimulation of platelet production in such patients. In experimental studies, TPO-RA was shown to stimulate production of platelets in both the normal as well as injured bone marrow [3, 13].
The pathogenetic mechanisms in ITP are heterogeneous and the proposed mechanisms are (1) antibody-mediated destruction, (2) T cell-mediated destruction, and (3) megakaryocyte injury/suppression . It is likely that one or many mechanisms may operate in a single patient and the response to therapy may depend upon the dominant underlying mechanisms. We have previously shown that patients who had evidence of bone marrow megakaryocytic abnormality were less likely to respond to eltrombopag . Hence it can be assumed that the response to a particular agent may depend upon the predominant mechanism underlying the pathogenesis of thrombocytopenia in ITP.
At present, the initial choice of therapy in newly diagnosed ITP patients is not individualised and steroid is arbitrarily given to all patients of ITP who need treatment. With addition of knowledge about different underlying mechanisms of thrombocytopenia in ITP, it is imperative to use other agents alone or in combination with steroids in order to target different pathogenetic mechanisms. While the specific ideal initial treatment is a matter of future endeavours, combination therapy including steroid with eltrombopag may be chosen as initial treatment in newly diagnosed ITP patients, or eltrombopag may promptly be chosen as agent of choice in case patients do not respond to steroid within 2 weeks. Study population is biased because it did not include other non-responders who opted for other choices.
Our study has demerits in that it is a single-centre study, has small sample size and lacks long-term safety profile. This manuscript is intended to present our findings that there is a possible role of eltrombopag in a subgroup of newly diagnosed ITP patients and in no way it recommends the use of eltrombopag in all newly diagnosed ITP patients. However, the response to eltrombopag in newly diagnosed steroid non-responsive ITP patients in the present study sets a platform for a longer study on a larger number of patients to substantiate the role of eltrombopag in these patients.
Conflict of interest