Eltrombopag Can Achieve Treatment Free Remission as Upfront Therapy for Patient with Immune Thrombocytopenia

Abstract

Immune Thrombocytopenic purpura (ITP) is an immune mediated thrombocytopenia caused by autoantibodies directed against platelet antigens which leads to destruction of the platelets by the spleen and inability of the bone marrow to restore normal counts. The main treatment for ITP is immunosuppressive medication and the first line treatment is glucocorticoids, intravenous immune globulin (IVIG) and Intravenous anti-D immune globulin. Here we report a 45-year old lady who was diagnosed with ITP and achieved treatment free remission after with Eltrombopag as upfront.

Background

Immune thrombocytopenic purpura (ITP) is a disorder characterized by isolated decrease in platelets count with peripheral blood platelet count <100 × 10⁹/L in the absence of other causes that may be associated with thrombocytopenia, ¹ and it happens due to antibody induced platelet destruction and impaired platelet synthesis from the bone marrow. ITP can be divided to 3 categories depending on the cause and it includes the primary ITP which is acquired immune thrombocytopenia due to autoimmune mechanisms leading to platelet destruction and platelet underproduction that is not triggered by an apparent associated condition, Secondary ITP which is ITP associated with another condition such as Chronic lymphocytic leukemia, Systemic lupus erythematosus, Antiphospholipid syndrome, Common variable immune deficiency, Autoimmune lymphoproliferative syndrome, Selective IgA deficiency, Measles, mumps and rubella (MMR) vaccination, Helicobacter pylori infection, HIV infection, Hepatitis C virus (HCV) infection, Cytomegalovirus (CMV) infection, Varicella zoster virus (VZV) infection and the third category is Drug-induced immune thrombocytopenia which is thrombocytopenia due to drug-dependent platelet antibodies that cause platelet destruction.

According to the consensus criteria of ITP international working group, this disease can be divided into 3 categories which is; newly diagnosed ITP (upto 3 months from diagnosis), persistent ITP (3-12 months of ITP duration), and chronic ITP (>12 months). ² The clinical presentation of ITP can range from being incidental finding during routine lab testing with platelets (PLT) count of <100 000/microL ² or bleeding of the skin and mucosal surfaces which can be manifested as Petechiae, Purpura, Epistaxis or sever bleeding like intracranial hemorrhage (ICH), overt gastrointestinal bleeding, severe menstrual bleeding and hematuria.

The Case

We report a 44-year old female with no previous medical illness, found to have low platelets count during pre-operative assessment for elective hernia repair, with no history of bleeding from any site including the mucosal surfaces and she denied any history of recent infection or recent medication intake in addition to that review of system was unremarkable except mild pain at the site of the hernia which is on and off. On physical exam the patient was hemodynamically stable with no skin discoloration, abdominal exam revealed umbilical hernia with no hepatomegaly or splenomegaly.

Lab investigation showed thrombocytopenia with PLT of 19 × 10^3 (150-400 × 10^3), Hemoglobulin (HB) level was 10.5 gm/dL (12-15 gm/dL), white blood cells (WBC) 5.8 × 10^3 (4-10 × 10^3), with normal liver and kidney function tests, normal thyroid function and normal B12 level, then peripheral smear showed Mild hypochromic microcytic anemia with anisopoikilocytosis including some scattered ovalocytes and few schistocytes, and Severe thrombocytopenia, us abdomen was done it showed normal size spleen. Hepatitis serology was negative and autoimmune disease work up was done it came back positive for anti-nuclear antibody (1:40) but negative for anti-double stranded DNA, anti-cardiolipin, anti-phospholipid, anti CCP and anti-rheumatoid factor.

The patient was managed as outpatient as she remained stable with no bleeding, started on Eltrombopag 25 mg and maintained on 50 mg Daily for 2 months and during this time platelets count was improving and then the dose was decreased to 50 mg alternating with 25 mg for another 2 months then the dose was decreased to 25 mg daily for 2 weeks then the dose was decreased to 25 mg weekly till discontinuation and patient remains in complete remission till now (11 months).

Discussion

The main goal for treatment of patients with ITP is to secure hemostasis rather than bringing platelets count back to normal.^3,4 Treatment options for patients with ITP should consider the severity of the illness and the age of the patient as well as life style, because the bleeding risk and the hemorrhagic fatality rate increase with age. ⁵ Most of the serious bleeding events has been reported to occur in adults with ITP who have platelet counts less than 30 × 10⁹/L. ⁶ As per American society of hematology (ASH) guidelines which was published in 2019 there was a lack of evidence to support strong recommendations for various management approaches for patient with ITP. ⁷

The current recommendations for treatment of patients with newly diagnosed ITP depends on platelets count and presence and absence of bleeding; For patients – with platelet count of <30 × 10⁹/L – who are asymptomatic or have minor mucocutaneous bleeding ASH guideline panel suggests treatment with corticosteroids which include either Prednisone (0.5-2.0 mg/kg per day) or Dexamethasone (40 mg per day) and thrombopoietin receptor agonist (TPO-RA) was recommended for patients who have ITP for ⩾3 months who are corticosteroid-dependent or unresponsive to corticosteroids. ⁷

TPO-RA are thrombopoietin analogs which enhance the activation, proliferation and maturation process of megakaryocytes, resulting in an increase in total platelets counts. There are 3 TPO-RAs that have been proven to be effective in the treatment of ITP in multiple phase III studies^8-10; ‘Romiplostim (Nplate, Amgen, Thousand Oaks, CA, USA) is a peptide TPO-RA administered subcutaneously on a weekly schedule and Eltrombopag (Promacta, Novartis, Basel, Switzerland) and Avatrombopag (Doptelet, Dova, Durham, NC, USA) are small molecule TPO-RAs administered orally on a once-daily schedule’.

Eltrombopag is a thrombopoietin receptor agonist currently approved for the treatment of chronic ITP in adults and pediatrics populations, however; this medication is the only United states Food and Drug Administration-approved thrombopoietin receptor agonist for the treatment of chronic ITP in children and it is widely used as second line agent in this age group, in a recent retrospective study ¹¹ which focused on the use of this drug in pediatrics population in 17 centres in Italy showed that the prevalence of Eltrombopage use was 19% and 55% of the study population never required any concomitant other agent use to achieve target platelet count. In addition to that, it has been reported in the literature for treatment of patients with acute or persistent ITP as it was used in 1 study as combination with high-dose dexamethasone as first-line treatment for newly diagnosed immune thrombocytopenia ¹² and the results showed the proportion of patients with platelet count ⩾50 × 10⁹/L at 6 months was 75% with the addition of Eltrombopag versus 37% reported with dexamethasone alone, and another study which used Eltrombopag plus high-dose dexamethasone with low-dose rituximab for newly diagnosed patients with immune thrombocytopenia ¹³ and the results showed probability of relapse-free survival of 79% at 2 years.

Sustained response to TPO-RAs was described in the literature in a retrospective study ¹⁴ in which the medication was used to treat adult patients with ITP not as first line, and the medication was discontinued later due to different reasons which includes persistent response despite a reduction in dose over time platelet count >400 × 10⁹/L, patient’s request, elevated aspartate aminotransferase, diarrhea, thrombosis and other reasons and the response was sustained in 26 patient out of 49 patient who were followed after the drug discontinuation. However, the exact mechanism for this response is still not well understood and there are multiple explanations; in 1 study the antiplatelets antibody was decreasing during the treatment with TPO-RAs and it was postulated that with continues exposure of the body immune system to platelets antigen the immune system will restore immune tolerance.^15-18

In our case the patient refused to take steroids and IVIG due to the possible side effects of both agents and after discussion with her about Eltrombopage and the possible side effects she agreed to start on it and to be followed as outpatient; during the follow up laboratory investigations showed improvement of platelets count and it came back to normal and she was maintained on complete remission without relapse during the treatment time which continued for 6 months then the medication was stopped and the patient was followed for 11 months with no drop in platelets count again.

Conclusion

ITP management still challenging and large number of patients usually receive the treatment as inpatient and they are at risk of the side effects of the currently used treatment. The use of Eltrombopag – as first line treatment for selected cases – will be more convenient as most of the patient has good tolerance to this medication which can be given as outpatient, however, this still needs to be studied more and specific criteria for the use of Eltrombopag as upfront to be figured out.