Splenectomy Outcomes in Relapsed or Refractory Immune Thrombocytopenia According to First-Line Intravenous Immunoglobulin Response

Introduction: Although splenectomy has long been second-line option for immune thrombocytopenia (ITP) patients, an indicator that reliably predicts the efficacy of splenectomy is still being explored. We investigated the treatment outcomes of splenectomy as a second-line therapy for relapsed/refractory ITP according to first-line intravenous immunoglobulin (IVIG) responses. Methods: Fifty-two adult patients treated with splenectomy as second-line therapy for ITP between 2009 and 2019 were included, and they were classified according to first-line IVIG responses (no response to IVIG: non-responders; only transient IVIG response shorter than 4 weeks: poor responders; IVIG response for a longer period; stable responders). The efficacy of splenectomy was analyzed in the three subgroups. Results: Of the 52 patients, 10 were IVIG non-responders, 34 were poor responders, and the remaining eight were stable responders. Response to splenectomy was observed in 50.0% of IVIG non-responders, 94.1% of poor responders, and 100% of stable responders (p = 0.0030). Among the 45 patients who responded to splenectomy, 51.1% relapsed subsequently, and a significantly lower relapse rate was noted in the stable IVIG responders (12.5%, p = 0.0220) than in non-responders (60.0%) and poor responders (59.4%). Conclusions: First-line IVIG response is indicated as a useful predictive factor for response to splenectomy.

Catastrophic anti-phospholipid syndrome with Libman-Sacks endocarditis following eltrombopag therapy for immune thrombocytopenic purpura: A case report

Background Immune thrombocytopenic purpura (ITP) is an autoimmune disease, with accelerated destruction of platelets, estimated to affect 1.6–3.9 in 100,000 adults every year in the European Union. Glucocorticoids and intravenous immunoglobulins are common drug therapies. In refractory cases, drugs that enhance thrombopoiesis may be used. Eltrombopag is a thrombopoietin receptor agonist, known to increase platelet count in patients with refractory ITP. Thrombotic adverse events have been described in association with Eltrombopag administration. Case report A young female patient of Ethiopian ancestry with systemic lupus erythematosus, triple Antiphospholipid (APLA) positive serology and refractory ITP who received Eltrombopag and 2 weeks later developed catastrophic APLA syndrome with severe Libman-Sacks endocarditis of the mitral and aortic valves, multiple intracerebral infracts and arterial thrombosis of the left upper limb. Conclusion Eltrombopag is a salvage drug, used in refractory ITP. Thrombotic adverse events, some of which may be life-threatening, are a possible complication, especially in high-risk patients.

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.

Refractory Immune Mediated ITP in a Patient with Metastatic Melanoma

Background: Immune check point inhibitors have changed the treatment landscape of many tumors including melanoma. They disrupt the immunoinhibitory signals mediated by programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to use the body's immune system to destroy the tumor. Consequently, they also predispose patients to immune related toxicity which may affect any organ, commonly skin, gastrointestinal, hepatic, pulmonary and endocrine. Hematological immune-related adverse events are less common and include neutropenia, autoimmune hemolytic anemia, immune thrombocytopenia (ITP) and aplastic anemia. Herein we present a case of refractory ITP in a patient receiving immunotherapy for metastatic malignant melanoma. Case Presentation: A 54-year-old female with metastatic melanoma harboring the BRAF V600E was started on ipilimumab and nivolumab. After 3 cycles of immunotherapy, she was found to have sudden onset thrombocytopenia requiring hospital admission. Complete blood counts showed platelet counts10k/mcL, hemoglobin 13.0 g/dL and white blood cell 4.1 K/uL. She did not manifest any overt bleeding or bruising on history and exam. There was no evidence of hemolysis on labs and peripheral blood smear; thrombotic microangiopathy was ruled out. She received high dose dexamethasone 40 mg intravenous daily and 1 mg/kg intravenous immune globulin daily for three days for suspected ITP due to immunotherapy. Her platelet counts did not improve and therefore a bone marrow biopsy was performed which revealed a normocellular marrow without evidence of melanoma. Imaging revealed excellent radiological response; it was decided to hold further doses of immunotherapy due to severe thrombocytopenia. She received rituximab 375 mg/m 2, with no response and platelet counts continued to between 2-5 K/mcL and required daily platelet transfusions. Romiplostim was initiated which improved platelet count to 10K/mcL and she was discharged. The following day her platelet counts dropped to 5K/mcL and she was sent back to the emergency room where she received 1 unit of platelet transfusion. Unfortunately, she developed a cold limb and was found to have a complete occlusion of the right distal popliteal artery and left tibio-peroneal trunk. Initiation of heparin infusion was discussed with the patient, however due to the significant bleeding risk from refractory ITP, the patient decided to pursue comfort measures only and was discharged home for hospice care. Discussion: About 0.5% of metastatic melanoma patients experience immune thrombocytopenia, deaths caused by this severe adverse event are even rarer. It is postulated that the activation of CD4+ helper T cells and CD8+ cytotoxic T cells can result in the damage to hematopoietic stem cells. Furthermore, nivolumab induced increased production of platelet-specific IgG autoantibodies also promote platelet destruction. Diagnosis is particularly challenging due lack of specific test or markers, and it remains a diagnosis of exclusion. The risk of bleeding, arterial thromboembolism and venous thrombosis is higher in ITP patients. ITP due to immunotherapy may be profound and refractory. One may consider the use of second line agents, such as TPO mimetics earlier in these patients. Conclusions: Our case highlights refractory ITP as a serious immune related adverse event that failed several lines of treatment strategies. Early diagnosis and combination treatment measures early in the course of the disease is imperative to mitigate associated morbidity and mortality. Combination of steroids immunoglobulins and second line agents may be warranted in some cases, and earlier use of tier 2 agents such as azathioprine should also be considered. Disclosures No relevant conflicts of interest to declare.

Incidence and outcomes of refractory immune thrombocytopenic purpura in children: a retrospective study in a single institution

Treatment of children with refractory immune thrombocytopenic purpura (ITP) is challenging and poorly established. We retrospectively reviewed the clinical data of 87 patients under the age of 16 years who were diagnosed with ITP from April 1998 to March 2017 in our institution. Refractory ITP was defined as a platelet count of < 50 × 109/L at 14 days after receiving intravenous immunoglobulin (IVIG) and prednisolone. We presumed that there was a pathophysiological overlap between refractory ITP and refractory thrombocytopenia (RT): a subtype of refractory cytopenia of childhood (RCC). Immunosuppressive therapies including anti-thymocyte globulin and cyclosporine (CsA) have been adopted for children with RCC in Japan. Thus, from 2009 onwards, we changed the diagnosis from refractory ITP to RT and introduced CsA for refractory ITP/RT. Nine of 42 patients developed refractory ITP in the 1998–2008 group, who received conventional treatments such as IVIG and steroid therapy. Eight of 45 patients developed refractory ITP in the 2009–2017 group, who received CsA with or without IVIG therapy. The response rate at three years after diagnosis was significantly higher in the 2009–2017 group (98%) than in the 1998–2008 group (83%) (p = 0.019). In conclusion, our strategy of introducing CsA for refractory ITP/RT contributed to better outcomes.

Rapid response to mycophenolate mofetil in combination with romiplostim in a case of severe refractory immune thrombocytopenia post COVID-19 vaccination

Vaccine mediated immune mediated thrombocytopenia (ITP) is an exceedingly rare. We present a 25-year-old female who developed severe refractory ITP with multiple active bleeding sites post second dose of COVID vaccination. She was treated with a combination of Romiplostim and Mycophenolate mofetil that resulted in rapid platelet count recovery.

A modified regimen of low-dose rituximab therapy for patients with refractory immune thrombocytopenia associated with systemic lupus erythematosus

Background: Severe and refractory immune thrombocytopenia (ITP) affects the life expectancy of patients with systemic lupus erythematosus (SLE) and poses a challenge in their clinical management. This intervention study employed a small sample size to evaluate the efficacy and safety of a modified low-dose rituximab (RTX) regimen in patients with SLE-associated refractory ITP. Methods: Eight patients with severe SLE-associated refractory ITP were enrolled in this intervention study. They received an infusion of intravenous RTX (200 mg) on days 1 and 15. The dose of corticosteroids (prescribed previously) was gradually tapered, and immunosuppressants were withdrawn. Patients were followed up at 1, 3, 6, and 12 months; platelet counts, other laboratory indicators, and side effects were recorded. We used intention-to-treat analysis to calculate the response rate. Results: Seven participants (87.5%) completed the study. At 1 month, two patients (25.0%) achieved partial response (PR); the PR rate increased to 87.5% at 3 months. At 6 months, three patients (37.5%) achieved complete response (CR). However, the CR rate dropped to 25.0% at 12 months. The overall responses (ORs) were 25.0% (2/8), 87.5% (7/8), 75.0%(6/8), and 75.0%(6/8) at 1, 3, 6, and 12 months, respectively. Two patients developed a mild infusion reaction and one discontinued the study due to herpes zoster virus infection and an allergic reaction 2 weeks after the first dose of RTX. Conclusion: Modified low-dose RTX therapy (two infusions of 200 mg every 2 weeks) could be a promising new option for patients with SLE-associated refractory ITP with a satisfactory response rate.

Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study

Management of immune thrombocytopenia (ITP) during pregnancy can be challenging because treatment choices are limited. Thrombopoietin receptor agonists (Tpo-RAs), which likely cross the placenta, are not recommended during pregnancy. To better assess the safety and efficacy of off-label use of Tpo-RAs during pregnancy, a multicenter observational and retrospective study was conducted. Results from 15 pregnant women with ITP (pregnancies, n = 17; neonates, n = 18) treated with either eltrombopag (n = 8) or romiplostim (n = 7) during pregnancy, including 2 patients with secondary ITP, were analyzed. Median time of Tpo-RA exposure during pregnancy was 4.4 weeks (range, 1-39 weeks); the indication for starting Tpo-RAs was preparation for delivery in 10 (58%) of 17 pregnancies, whereas 4 had chronic refractory symptomatic ITP and 3 were receiving eltrombopag when pregnancy started. Regarding safety, neither thromboembolic events among mothers nor Tpo-RA–related fetal or neonatal complications were observed, except for 1 case of neonatal thrombocytosis. Response to Tpo-RAs was achieved in 77% of cases, mostly in combination with concomitant ITP therapy (70% of responders). On the basis of these preliminary findings, temporary off-label use of Tpo-RAs for severe and/or refractory ITP during pregnancy seems safe for both mother and neonate and is likely to be helpful, especially before delivery.

Decision Aid to Support Shared Decision Making in Pediatric Refractory Immune Thrombocytopenia

Background: Immune thrombocytopenia (ITP) is characterized by isolated low platelet count in the absence of other etiologies for thrombocytopenia. Despite published guidelines (Neunert, Blood Adv 2019), controversy exists in the management of patients with pediatric refractory ITP. Data on second-line treatment approaches is limited and no randomized controlled trials exist for this patient group. A comparative-effectiveness trial demonstrated variation in prescribing practices, with parental or patient preference involved in decision making in 55% of cases (Grace, Am J Hematol, 2018). Despite this data, no qualitative studies have been done to explore the patient experience. We aim for the first time to explore thematic areas surrounding rationale for treatment choice for patients with refractory ITP from the patient/parent point of view, as a first step to creating a decision aid. Our goal is that this aid will inform individuals with regards to options, encourage engagement of patients in decision, and assist patients with processing their preferences so they can make choices reflective of their values. Methods: Purposeful sampling identified participants locally from Columbia University Medical Center as well as nationally through the Platelet Disorder Support Association. Focus groups were conducted with an average of 5-7 parents of children with ITP in each group, and each lasting approximately 90 minutes. A written guide with open-ended questions was created to elicit participant opinions and foster guided discussion between them, illuminating particular concepts and permitting researchers to gain an understanding of patient experiences in the context of their own lives. Focus groups were audio recorded and transcribed. The de-identified transcripts were uploaded into Dedoose, a qualitative software. A thematic analysis was conducted to identify the nature, strength and prevalence of key concepts. Results: Three major themes were identified with regards to treatment choice for second line therapy: 'Experiences with Treatment Decision Making', 'Factors Important in Decision Making', and 'Concept of Remission'. Excerpts demonstrating findings from each theme, as well as some of the variability amongst participants' opinions, are shown in Table 1. With regards to experiences with treatment decision making, many parents expressed that they felt their hematologist presented the options with adequate descriptions of risks and benefits, though the extent to which parents seem to feel included in the decision was not consistent. Often, even if presented with options, parents did not view themselves as critical decision makers and some patients still reported not feeling well-educated about options. Additionally, many participants reported that they went through a "trial and error" process with regards to different second-line therapies, with no notable or specific conversations defining any one person's experience. Discussion: The data collected suggests that parents of children with refractory ITP have strong ideas about communications around their treatment options. The factors important to decision making appeared consistent between participants, and would provide valuable input in the ultimate decision making tool and also be important to capture in future research trials of different agents. Of interest, the concept of remission came up frequently, and did not have the meaning that the research team expected. Participants noted that the term had a negative connotation, and meant only that there was a possibility of the disease returning. They felt that the term gave a false sense of relief, because their disease was unlikely to be truly cured. This was emphasized as a value in treatment selection. The information provided by these focus groups indicates that physicians' views on choosing therapies "based on patient preference" are not completely aligned with the patient experience. Additional focus group work, creation of a patient decision-aid, and inclusion of patient relevant outcomes in research will hopefully close this gap. We ultimately hope to create a clinical decision aid developed from input of these focus groups in order to increase patient understanding of their options, improve targeted treatment effects with regards to patient-related outcomes of importance, and help to guide management decisions. Disclosures Neunert: Platelet Disorder Support Association: Research Funding.