Effectiveness of total therapy in immune thrombocytopenia purpura: case series

Nisarg R Hajariwala, Hinal S Panchal, Nira Amin, Deeksha A Singh

1Department of Clinical Pharmacy, HCG Cancer Center, Vadodara, Gujarat, India.2Department of Pharmacy Practice, Parul University, Vadodara, Gujarat, India.

Abstract Immune Thrombocytopenic purpura (ITP) is a haematologic immune-mediated disorder in which the amount of platelet in the blood decreases abnormally.Single-agent therapies for ITP have not proven successful in achieving long-term remission, with relapse occurring in about half of the patients (p/t).Treatment options which include Rituximab with Dexamethasone as frontline therapy, have durable response rates ranging from 58% to 76%.In this study, we have used ‘Total therapy’ as treatment which includes low-dose Rituximab in combination with Thrombopoietin receptor agonist (TPO-RA) (Romiplostim) and high-dose Dexamethasone.In this case series study, each patient received romiplostim (250 mcg weekly s/c, 4 doses) in combination with low-dose rituximab (100 mg weekly IV, 4 doses) and high-dose dexamethasone (40 mg IV on days 1–4 and days 15–18).This treatment combination demonstrated rapid response rates and a low rate of side effects, making it a good alternative for individuals with ITP.

Keywords: haematological; platelet; immune thrombocytopenia purpura (ITP); total therapy; TPO-RA

Introduction

Immune thrombocytopenic purpura (ITP) is a common haematologic immune-mediated disorder.It is a blood disorder in which the amount of platelet in the blood decreases abnormally [1].Nearly one in every 10,000 people in the world are affected by ITP.ITP becomes more common as people get older, as it is more prevalent among people over 60 years.Patients over 60 years have a considerably higher 5-year mortality risk from bleeding than patients under 40 years old, 47.8 % against 2.2 % respectively, in patients with severe thrombocytopenia [2].There are 2.6 incidences of chronic ITP in women for every case involving a man among adults (ages 30–60).The male to female ratio among children is nearly equal, with 52 % male and 48 % female [3].ITP is commonly diagnosed in people having platelet counts ＜ 100 × 103/μL.

The risk of spontaneous haemorrhage associated with a low platelet count determines the prognosis.There is a 5% expected risk of serious haemorrhagic episodes in the patients suffering from ITP once in their lifetime.Patients without symptoms who have platelets counts above 30×103/μL should generally not be treated unless they have increased risk of bleeding for any symptoms [2].The mechanism of action of the TPO-RA is thought to be due to increased platelet production, both TPO-RA has also been described to have immunomodulatory effects, with greater regulatory T-and B-cell effects in patients on TPO-RA [4].Platelet deficiency can be caused by the decrease in its synthesis, immune-mediated destruction, or increased splenic sequestration of platelet [5, 7].The key characteristic in the pathophysiology of primary ITP is the lack of immunological tolerance to platelet-specific antigens [6].Frontline therapy includes corticosteroids, intravenous immunoglobulin (IVIG) or anti-D immunoglobulin.The characteristic of ITP includes platelet counts less than 10,000 therefore lower the platelet counts greater the risk of bleeding, mucocutaneous lesions such as small red or purple spots caused by bleeding into the skin and discoloration of the skin resulting from bleeding underneath, typically caused by bruising, epistaxis (nose bleeding), easy bruising of the skin, and gums bleeding.Some patients, however, may experience more severe bleeding, which may be cutaneous, mucosal, gastrointestinal, or even cerebral (0.1–0.5 %) [7].The ‘Total therapy’ treatment consists of a combination of high-dose steroids, TPO-RAs, and low dose-Rituximab [8].This treatment combination showed rapid response rates and a low frequency of side effects, making it an appealing alternative for patients with ITP with significant bleeding [9].

Informed consent was obtained from the patients for the case to be studied and published.Approval from the Ethics Committee was granted.

Case Series

Patient 1

A 40 years old male patient was visited to the department of Haematology at HCG cancer centre Vadodara with the newly diagnosed ITP.Reports were done for Bone marrow aspiration and biopsy which showed normocellular marrow with megakaryocytic hyperplasia.CBC report showed platelet count 15×103/μL.Treatment was provided (Table 1) 1stCycle was started on 6thApril 2021.Then 2ndCycle was given on 13thApril 2021 and CBC report showed platelet count 213×103/μL.Followed by the 3rdCycle on 20thApril 2021 after which CBC report showed platelet counts 101×103/μL.Later 4thCycle was given on 27thApril 2021.The patient was called for follow-up after a week which showed the platelet counts 75×103/μL.

Patient 2

A 16 years old male patient was visited to the department of Haematology at HCG cancer centre Vadodara with the history of ITP since 10 years.CBC report done on 29thDec, 2013 shows platelet count 15 x 103/μL.Bone marrow aspiration report of Jan 2014 showed a mild increase in megakaryocytes.Patient underwent steroid trial in 2014 and got some response but lost response on stopping steroids.Patient re-started steroids therapy and started to get the response.The patient stopped steroid therapy due to obesity and weight gain.There after patient started ayurvedic treatment since 2015 and stopped after 3 years.During his ayurvedic treatment his platelet use to remain in between 9 x 103/μL to 50 x 103/μL.And then was admitted to HCG for total therapy and supportive medical management on 11thMarch, 2021.CBC report was done on 04thMarch, 2021 shows platelet count 9 x 103/μL.1stCycle was started on 11thMarch, 2021 (Table 1).Then 2ndCycle was given on 18thMarch, 2021 & CBC report was done which showed platelet counts 208 x 103/μL.On 3rdCycle (25thMarch, 21) and 4thCycle (01stApril, 21) CBC report was done which showed platelet counts 105 x 103/μL and 184 x 103/μL.

Table 1 Treatment chart of 5 patients diagnosed with immune thrombocytopenia treated with the Total Therapy i.e., combination of high-dose Dexamethasone combined with TPO-RA (Romiplostim) and low-dose Rituximab

Patient 3

A 51 years old male patient was visited to the department of Haematology at HCG cancer centre Vadodara with the history of generalized weakness and body ache, low grade fever, blood transfusion was done in last one week.Patient was admitted at Anand and he was found to have thrombocytopenia, he was treated with oral steroids and other supportive medicines.Patient did not have any history of blood loss or red color spots over body.CBC reports showed platelet count 6 x 103/μL on 10thMay, 2021.Bone marrow aspiration report shows increase in megakaryocytes with mildly hypercellular marrow.So, 1stcycle was started on 10thMay, 2021(Table 1).There after 2ndcycle was done on 18thMay, 2021 & CBC reports showed platelet counts 18 x 103/μL.In 3rdCycle (25thMay, 21) and 4thCycle (01stJune, 21) CBC report was done which showed platelet count 20 x 103/μL and 229 x 103/μL.

Patient 4

A 45 years old female patient was visited to the department of Haematology at HCG cancer centre Vadodara with the newly diagnosed ITP and had history of COVID 19 infection in April 2021.patient presented with c/o red patches all over body and heavy menstrual bleeding.Patient was admitted to HCG for total therapy and supportive medical management on 10thJuly 2021.CBC report done on 10thJuly 2021 showed platelet counts 4 x 103/μL.1stCycle was started on 10thJuly 2021(Table 1) and CBC report was done on 11th, 12thand 13thJuly showed platelet counts 6 x 103/μL, 23 x 103/μL and 42 x 103/μL respectively.Then 2ndCycle was given on 20thJuly 2021.Patient presented with c/o body ache and other symptoms are resolved.CBC report was done which showed platelet count 86 x 103/μL.On 3rdCycle (27thJuly, 21) and 4thCycle (03rdAugust, 21) CBC report was done which showed platelet counts 83 x 103/μL and 94 x 103/μL.

Patient 5

A 31 years old male patient was visited to the department of Heamatology at HCG cancer centre Vadodara with the newly diagnosed ITP and c/o of melaena, oral blisters and marked thrombocytopenia.Past medication history of patient showed that he was on steroid (Prednisolone) treatment but gave poor response.Then patient was admitted to HCG for total therapy and supportive medical management on 2ndOctober, 2021.CBC report done on 2ndOctober, 2021 shows platelet counts 7 x 103/μL.1stCycle was started on 2ndOctober, 2021.CBC report was done on 3rd, 4thand 5thOctober shows platelet counts 6 x 103/μL, 10 x 103/μL and 14 x 103/μL respctively.2ndCycle was given on 11thOctober 2021, patient presented with c/o maculo-papular eruptions over forehead, chest, back and itching.CBC report was done which showed platelet counts 319 x 103/μL.3rdCycle was given on 18thOctober 2021 and CBC report was done which showed platelet counts 443 x 103/μL.4thCycle was given on 25thOctober, 2021 and CBC report was done which showed platelet counts 248 x 103/μL.The patient was called for follow up after a week (08thNovember, 21) which showed the platelet counts 244 x 103/μL.

Discussion

In Immune thrombocytopenia (ITP) platelets are covered with auto antibodies to platelet membrane antigens, causing splenic sequestration and phagocytosis by mononuclear macrophages.This results to shortened life span of platelet in the circulation, leading to reduced amount of circulating platelet [10].ITP causes bleeding, easy bruising (purpura), bleeding in the mouth, hematochezia and blood extravasation from capillaries into the skin and mucous membranes (petechiae) [11].Benefit of employing comprehensive total therapy regimen is reduce remission of treatment, decrease in bleeding and use of concomitant medication.Fluctuating platelet counts, hyperglycemia, restlessness, bone marrow fibrosis, Thromboembolism, risk of clonal evolution, infections, hypo-gamma globulinemia will always remain a concern in ITP patient [4].In the United States, the age-adjusted prevalence of immune thrombocytopenic purpura (ITP) is estimated to be 9.5 per 100,000 people, whereas in Northern Europe, the annual incidence is 2.68 per 100,000 [12].In adults first line treatment with newly diagnosed ITP, as per ASH guideline, prolonged course (＞ 6 weeks) of prednisone in favor of a short course (≤ 6 weeks) and suggests either prednisone (0.5–2.0 mg/kg/day) or dexamethasone (40 mg/day for 4 days) as the type of corticosteroid for initial therapy.Second line therapy lasting ≥3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline suggests, Thrombopoietin receptor agonist (eltrombopag or romiplostim), Rituximab, Splenectomy.In children first line treatment with newly diagnosed ITP who have non-life-threatening mucosal bleeding and/or diminished health related quality of life, the ASH guideline corticosteroids longer than 7 days in favor of courses 7 days or shorter , and suggests prednisone (2–4 mg/kg/day; maximum, 120 mg daily, for 5–7 days) rather than dexamethasone (0.6 mg/kg/day; maximum, 40 mg/kg/day, for 4 days).Second line treatment lasting ≥ 3 months who have non-life-threatening mucosal bleeding and/or diminished health-related quality of life and do not respond to first-line treatment, the ASH guideline suggests, Thrombopoietin receptor agonist (eltrombopag or romiplostim) ,Rituximab, Splenectomy [13].In the study done by Wang H et al TPO-RAs have been recommended as a feasible agent to use in combination with rituximab to generate a rapid increase in platelet count.Because rituximab and TPO-RAs have separate mechanisms of action, so the synergistic effects of such combination can be more effective.This study shows similar results when compared to our study which also has synergistic effect by combining as the TPO-RAs & Rituximab.The platelet counts were monitored on regular intervals as shown in Table 2 during the treatment.And outcomes of patients therapy is shown in (Figure 1).To avoid thrombocytosis, romiplostim was skipped when platelet counts were ＞ 250 x 103/μL.When rituximab and romiplostim are used as a single therapy, both lead to thrombocytosis.Where as in our case total therapy has lesser risk of thrombocytosis [14].

Figure 1 Outcomes of 5 patients diagnosed with ITP treated with the Total Therapy i.e., combination of high-dose Dexamethasone combined with TPO-RA (Romiplostim) and low-dose Rituximab

In the last decade, new medicines, particularly thrombopoietin receptor agonists (TPO-RAs) and rituximab, have reduced the use of splenectomy as a second-line treatment.In the study performed by F.Palandri et al, i.e., retrospective cohort study on 557 ITP patients where they concluded that splenectomy continues to be the therapeutic option with the best response rates and the lowest relapse rate.Whereas in our study TPO-RA and rituximab is used as a first line treatment with greater effectivness and the response of each patient was monitored as shown in Table 3 [12].

Table 2 Platelet counts of 5 patients diagnosed with ITP treated with the Total Therapy i.e., combination of high-dose Dexamethasone combined with TPO-RA (Romiplostim) and low-dose Rituximab

Table 3 Characteristics and outcomes of 5 patients diagnosed with Immune Thrombocytopenia treated with the Total Therapy i.e., combination of high-dose Dexamethasone combined with TPO-RA (Romiplostim) and low-dose Rituximab

Conclusion

In this case series we evaluated that how high-dose dexamethasone combined with TPO-RA (romiplostim) and low-dose rituximab is effective in newly diagnosed ITP patients.This treatment combination demonstrated rapid response rates and a low rate of side effects, making it a good alternative for individuals with ITP.In summary, we have found that this combination is a safe, highly effective, feasible and relatively durable treatment alternative for ITP.

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