Second-line Therapy For Immune Thrombocytopenia Research Articles

Treatment opportunities for refractory immune thrombocytopenia

Background. Primary immune thrombocytopenia (ITP) is an orphan disease characterized by decreased platelet count in the peripheral blood which in some cases can cause bleeding of varying severity. Currently, the use of thrombopoietin receptor agonists (TPO-RAs) is recommended as the second line therapy for ITP as it allows to achieve high platelet response (PR), including complete, in 73 % of cases of chronic ITP and in 87 % of cases of newly diagnosed disease. The mechanism of action differs for different TPO-RAs. Given this fact, in cases of resistance or intolerance to therapy with one TPO-RA, attempts are made to switch to another. The effectiveness of this approach for overcoming ITP resistance varies from 50 to 93 % according to various publications. Aim. To assess the ability to achieve and maintain PR by switching from one TPO-RA to another in cases of resistance to the previous TPO-RA used in the second or subsequent lines of therapy. Materials and methods. The analysis included 59 patients who were resistant (in 2 cases intolerance was also noted) to TPO-RA therapy (received after standard therapy) who were prescribed TPO-RA treatment with a different mechanism of action: switch from romiplostim to eltrombopag (25 patients) or vice versa (34 patients). Both groups were comparable in terms of demographic characteristics and median platelet level at the time of TPO-RA switching. Results. PR was obtained in 76 % of cases, including complete response in 54 %, as a result of switching from one TPO-RA to another in 59 patients. Among 34 patients switched from eltrombopag to romiplostim, PR was achieved in 31 (91 %) patients, including complete response in 22 (65 %). Romiplostim was switched to eltrombopag in 25 patients, PR was achieved in 14 (56 %) with complete response in 10 (40 %). Conclusion. The study showed that PR can be achieved and maintained through switching from one TPO-RA to an alternative.

Real-world experience with fostamatinib in patients with immune thrombocytopenia: Results of an observational study (FORTE).

e23289 Background: Immune thrombocytopenia (ITP) is an autoantibody-mediated disease in which platelets are prematurely phagocytosed by Fcg-receptor-bearing macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Corticosteroids (CS) are used to suppress the immune response, but long-term use carries a heavy burden of toxicity. Subsequent treatments for ITP include fostamatinib, a potent oral SYK inhibitor approved in 2018 based on two randomized, placebo-controlled, phase 3 trials. In trial patients, who received fostamatinib as second-line therapy following CS with or without immunoglobulins (IVIG), 25 of 32 (78%) patients achieved a platelet response of ≥50,000/µL, which was sustained for a median of 83% of treatment days. Here, we report real-world experience with fostamatinib as second-line therapy for ITP from a multi-center, prospective, observational study. Methods: The study (FORTE; NCT04904276) enrolled adult patients with ITP and an insufficient response to prior CS and/or IVIG. Patients were treated according to their clinician’s discretion, and data were collected for up to 12 months at clinic visits. Results: Sixteen patients were enrolled, and 15 were treated. Of the 15, 9 (60%) were female and the median age was 48 years (range, 20-92). 12 (80%) patients had prior CS and 6 (40%) prior IVIG. 7 (47%) patients completed the study and 8 discontinued treatment due to adverse events (4), lack of efficacy (2), and patient decision (2). After initiation of fostamatinib, 93% (14/15) of patients achieved ≥1 platelet count ≥50,000/μL. Median platelet count increased over time from 43,000/μL (IQR 19,000-105,000) at baseline to 167,000/μL (IQR 96,000-180,000) at Month 12. The median cumulative duration of elevated platelet count was 32 weeks (IQR 6.4-49.4). Concomitant CS were used by 7 (47%) patients at baseline, all of whom were able to taper as early as Month 1 and discontinue their dose by Month 3 in 4 patients, Month 6 in 2 patients, and Month 9 in 1 patient. Five patients had ITP-related AEs (4 Grade 1 and 1 Grade 2): gingival bleeding (2), mucosal haemorrhage (2), fatigue (1), contusion (3), headache (1) and epistaxis (1). There were 3 serious AEs in 2 patients: Grade 3 diarrhea in 1 and Grade 2 dyspnea and chills in 1. Overall safety results were consistent with previous studies of fostamatinib. Conclusions: Real world use of fostamatinib as documented in this observational study demonstrated efficacy and safety as second-line therapy for ITP. Fostamatinib allowed successful tapering and discontinuation of CS while maintaining platelet counts above 50,000/μL. Clinical trial information: NCT04904276 .

Romiplostim use in immune thrombocytopenia: Experience in Cuenca, Ecuador

Introduction. The international consensus and the American Society of Hematology guidelines from 2019 established thrombopoietin analogues as the second-line therapy for primary immune thrombocytopenia cases. Objectives. To describe romiplostim usefulness in patients with immune thrombocytopenia in a third-level hospital in Cuenca, Ecuador. Materials and methods. We conducted a descriptive and retrospective study in patients with immune thrombocytopenia treated with romiplostim. We evaluated the following variables: age, gender, previous therapies to romiplostim, dose, frequency, complications, change of thrombopoietin analogue, and treatment discontinuation. Results. We included 21 patients with immune thrombocytopenia treated with romiplostim, with a median age of 49 years. All patients received corticosteroids as first-line treatment. Three patients required longer administration intervals (over a week), with weekly doses lower than those recommended (< 1 μg/kg). Due to lack of efficacy, six patients replaced elthrombopag with romiplostim. Of the total, three suffered thrombotic complications: two had portal venous thrombosis, and one had pulmonary thromboembolism; five of the patients discontinued romiplostim scheme without resuming it. Conclusions. Romiplostim constitutes a convenient second-line therapy in immune thrombocytopenia. Despite the small sample size, romiplostim early use can minimize toxicities and infectious risks.

Efficacy and safety of avatrombopag in Chinese children with persistent and chronic primary immune thrombocytopenia: A multicentre observational retrospective study in China.

Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO-RA) that has been recently approved as a second-line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second-line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty-four (18 males) patients with a mean age of 6.3 (range: 1.9-15.3) years were enrolled. The median number of previous treatment types was four (range: 1-6), and 41.2% patients switched from other TPO-RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1-27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1-3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second-line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs.

Use of dapsone in chronic/refractory immune thrombocytopenic patients: A single center experience

Background: Dapsone is a second-line therapy for immune thrombocytopenia (ITP). It is cost-effective, with a response rate comparable to other drugs used as second-line therapy, such as azathioprine, danazol, cyclophosphamide, cyclosporine, vincristine, rituximab, and eltrombopag.&#x0D; Material and Methods: This retrospective study analyzed ten adult patients who presented to our hematology division outpatient clinic between March 2013 and July 2021, was diagnosed with chronic/refractory ITP, did not respond to first-line therapy, and used dapsone.&#x0D; Results: Eight (80%) patients were female, and 2 (20%) were male. The median age was 50 (range, 24-64) years. The mean pre-treatment platelet value was 12.8x109/L (range: 4-22.1x109/L). The median duration of symptoms before dapsone treatment was 60 (6-360) months. The median number of treatments received before dapsone was 4 (range: 3-6). All patients were routinely treated with oral dapsone 50 mg for two weeks, followed by 100 mg. The median time to treatment response was 39 (range: 14-90) days. The response rate was 60% (complete response 40%, partial response 20%). Asymptomatic anemia was observed as a side effect in only one patient.&#x0D; Conclusions: Based on these results, it can be speculated that dapsone is an effective, inexpensive, and well tolerated&#x0D; treatment option. Considering the economic status of developing countries, it seems very attractive&#x0D; to use dapsone as the second-line therapy for chronic/refractory ITP. To the best of our knowledge, this is the&#x0D; first study in Turkey on the use of dapsone for chronic/refractory ITP.

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

Objectives: 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: nonresponders; 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 nonresponders, 34 were poor responders, and the remaining 8 were stable responders. Response to splenectomy was observed in 50.0% of IVIG nonresponders, 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 nonresponders (60.0%) and poor responders (59.4%). Conclusions: First-line IVIG response is indicated as a useful predictive factor for response to splenectomy.

An Observational Study of Fostamatinib As Second Line Therapy in Adult Patients with Immune Thrombocytopenia (ITP) in Real-World Clinical Practice

Background: In immune thrombocytopenia (ITP), autoantibody-bound platelets are targeted for phagocytosis by Fcγ-receptors on macrophages in a spleen tyrosine kinase (SYK)-dependent signaling pathway. Fostamatinib is a potent oral SYK inhibitor that demonstrated efficacy for the treatment of ITP in two phase 3 randomized, placebo-controlled, double-blind studies and long-term durable responses in the phase 3 open-label extension study. In these studies, 146 patients with ITP were treated with fostamatinib, and 54% had a platelet response (platelet count ≥50,000/µL), which was maintained over a median of 86% of treatment days. These studies led to approval of fostamatinib in the US, Europe, and Canada as a therapy for chronic ITP in adult patients who have had an insufficient response to a prior treatment. Further, a post-hoc analysis showed that, in those who received fostamatinib as second-line therapy (following steroids ± immunoglobulins), 78% achieved a platelet response, which was maintained over a median of 83% of treatment days. 1 Adverse events (AEs) were reported in 72% of second-line patients and 86% of all patients, and common AEs were similar between second-line patients and the total patient population. 1, 2 Bleeding events were reported in 24% of second-line patients vs. 41% of all patients. The results of the post hoc analysis underscored the necessity for further evaluation of fostamatinib as a second-line therapy for ITP.We are conducting a multi-center, prospective, observational, two cohort study of fostamatinib as second-line therapy for the management of ITP in adult patients who have an insufficient response to prior steroids ± immunoglobulins.Aim: This study will evaluate clinical outcomes and safety of fostamatinib as second-line therapy for ITP in adult patients in real-world clinical practice. Patients will also be assessed for quality of life and utilization of health care resources during the study.Methods: The study (FORTE; NCT04904276; O-FOSTA-901) is being conducted at 10 sites across the US and will enroll 45 patients with ITP into 2 cohorts (see Figure). The study is registered at https://clinicaltrials.gov/ct2/show/NCT04904276. The study aims to enroll adult patients with a confirmed diagnosis of ITP and an inadequate response to prior steroids ± immunoglobulins. Patients who have received any prior ITP treatment other than steroids or immunoglobulins will be excluded. Patients who will initiate fostamatinib as second-line therapy at study entry will be enrolled into Cohort 1; patients currently receiving fostamatinib as second-line therapy with the intent to continue treatment will be enrolled in Cohort 2 (historical platelet counts will be retrospectively collected). Patients will be treated by their clinician at the clinician's discretion (not pre-specified by a study protocol).Primary outcome measures will include platelet count over time, duration of platelet count elevation, use of ITP rescue medication, changes in dosing, use of concomitant ITP medications, incidence of serious and ITP-related AEs, and quality of life. Quality of life assessments will utilize the SF-36v2 and ITP-PAQ. All data will be collected at regularly scheduled clinic visits according to the clinician's normal practice for 12 months or until fostamatinib is discontinued.Summary: This ongoing observational study of adult patients with ITP will enable further characterization of the risk/benefit profile of fostamatinib as a second-line treatment for ITP and will provide insight on how clinicians manage ITP in a real-world setting without the constraints of a clinical trial protocol.

Outcomes and Health Resource Utilization Among Second-Line Therapies for Immune Thrombocytopenia: A Provincial Retrospective Cohort Study

Introduction:Immune thrombocytopenia (ITP) is an immune-mediated disorder characterized by increased platelet destruction. Current guidelines recommend either rituximab, splenectomy, or thrombopoietin receptor agonist (TPO-RA) in chronic ITP patients who are unresponsive to first-line corticosteroids or who are corticosteroid-dependent. Though there are known practice variations in choice and timing of second-line therapy in Canada, there are scarce data comparing the outcomes and resource utilization in patients who received these second-line treatment strategies. In this multi-centre retrospective cohort study, we aim to identify differences in health services utilization and ITP-related outcomes in patients who received different second-line ITP therapies.Methods:Adults who received rituximab, splenectomy or TPO-RA as second-line therapy for ITP during 2012-2019 in the province of Alberta, Canada were identified via the provincial special drug access database. Institutional ethics board approval was obtained. We examined treatment patterns including sequencing of therapies and predictors of second-line therapies. Major outcomes documented included ITP-related hospitalizations (bleeding or infections), blood product utilization, major bleeding and thromboembolism, and all-cause mortality. Kaplan-Meier survival curves were used to estimate overall survival and the cumulative incidence of hospitalizations. Log-rank test was used to assess for differences between groups.Results:At the time of interim analysis, 189 adults with chronic ITP received second-line therapy. The median age at the time of second-line therapy was 58 years; 102 (54%) were female. Patients who received TPO-RA were significantly older than those who received rituximab or splenectomy (median 65 years vs 53 vs 49 years; P=0.0008). Rituximab was the most prescribed second-line therapy (108; 57%) followed by splenectomy (45; 24%) and TPO-RA (36; 19%) (Figure 1).Compared to recipients of rituximab, those who received TPO-RA had higher rates of hypertension (64% vs 33%, P=0.004), dyslipidemia (58% vs 20%, P <0.001), and prior history of myocardial infarction (22% vs 6%, P=0.02). On multivariable logistic regression, age (adjusted odds ratio [aOR] 1.03, 95% confidence interval [CI] 1.01-1.05, P=0.01) and a history of thromboembolism prior to second-line therapy (aOR 2.7, 95% 1.04-7.1, P=0.04) were significantly associated with TPO-RA prescription. Sex, rural residence, ITP etiology, major bleeding prior to second-line therapy, and abnormal bone marrow findings were not significant predictors of second-line therapy.During 773 person-years of follow-up, 23 deaths occurred, due to cardiac events (n=6), infections (n=5), malignancies (n=4), bleeding (n=3), and other or unclear causes (n=5). The 5-year overall survival was 88% (95% CI 82-94%), significantly shorter in recipients of second-line TPO-RA (80%) than rituximab (90%) and splenectomy (94%; log-rank P=0.04; Figure 2). The 5-year relapse-free survival was 55% (95% CI 46-65%), with no significant difference between treatment groups (log-rank P=0.8). Overall, 59 (31%) patients required ITP-related hospitalizations following second-line therapy. The median times to hospitalization were 5.1 years, 12.2 years, and not reached in patients receiving rituximab, splenectomy, and TPO-RA, respectively (log-rank P=0.1). Intravenous immunoglobulins and platelet transfusions were frequently utilized across all treatment groups (Table 2).DISCUSSION:Despite a myriad of therapeutic options for chronic ITP, patients still experience a high burden of hospitalization for bleeding or infections, and transfusion requirements. Patients with advanced age and a history of thromboembolism were more likely to receive TPO-RA as second-line ITP therapy. We did not observe a significant difference in relapse-free survival or ITP-related hospitalizations across different second-line therapies, although this may be limited by our sample size and duration of follow-up. At present, significant cost of TPO-RAs limits their availability as second-line therapy in many publicly funded healthcare systems. Real-world data are important in guiding future cost-effectiveness analysis to assess the impact of second-line therapies on the overall healthcare system. [Display omitted] DisclosuresSun: Shire: Consultancy; Octapharma: Consultancy, Research Funding; Pfizer: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy.

Second-Line Therapy for Immune Thrombocytopenia: Real-World Experience in Canada

BackgroundThe sequence of second-line therapy used for the treatment of immune thrombocytopenia (ITP) is variable. This study aimed to describe the types and sequences of second-line therapies for a large cohort of ITP patients in Canada. MethodsWe completed a retrospective cohort study of the McMaster ITP Registry. We included patients with primary or secondary ITP who had received one or more second-line therapies including any of the splenectomy, rituximab, danazol, dapsone, or thrombopoietin receptor agonists (TPO-RAs), or immunosuppressant medications. Immunosuppressant medications included azathioprine, cyclophosphamide, cyclosporine, or mycophenolate given alone or in combination. ResultsWe identified 204 ITP patients who had received one or more second-line therapies. The most common second-line therapies were immunosuppressant medications (n = 106; 52.0%), splenectomy (n = 106; 52.0%), TPO-RAs (n = 75; 36.8%), danazol (n = 73; 35.8%), and rituximab (n = 67; 32.8%). For patients who received only one second-line therapy (n = 88), the most common treatment was splenectomy (n = 28; 31.8%). For patients who received more than one second-line therapy (n = 116), the most common treatment sequence was splenectomy, followed by immunosuppressant medications (n = 7; 6.0%). Of the 154 evaluable patients at the end of follow-up, 69 (44.8%) achieved a complete platelet count response and 101 (65.5%) achieved a partial response. ConclusionImmunosuppressant medications and splenectomy are commonly used as second-line therapies for ITP in Canada. Treatment choices and the sequence of treatments were variable. RESUME Contexte La séquence de la thérapie de deuxième ligne utilisée pour le traitement de la thrombocytopénie immunitaire (PTI) est variable. Cette étude visait à décrire les types et les séquences des thérapies de deuxième ligne pour une large cohorte de patients atteints de PTI au Canada. MéthodesNous avons réalisé une étude de cohorte rétrospective du registre ITP de McMaster. Nous avons inclus des patients atteints de PTI primaire ou secondaire qui avaient reçu une ou plusieurs thérapies de deuxième ligne, y compris une splénectomie, du rituximab, du danazol, de la dapsone ou des agonistes des récepteurs de la thrombopoïétine (AR-TPO), ou des médicaments immunosuppresseurs. Les médicaments immunosuppresseurs comprennent l’azathioprine, le cyclophosphamide, la cyclosporine ou le mycophénolate, administrés seuls ou en combinaison. RésultatsNous avons identifié 204 patients atteints de PTI qui avaient reçu une ou plusieurs thérapies de seconde ligne. Les thérapies de deuxième ligne les plus courantes étaient les immunosuppresseurs (n = 106; 52.0%), la splénectomie (n = 106; 52.0%), les AR-TPO (n = 75; 36.8%), le danazol (n = 73; 35.8%) et le rituximab (n = 67; 32.8%). Pour les patients qui n’ont reçu qu’un seul traitement de deuxième intention (n = 88), le traitement le plus courant était la splénectomie (n = 28; 31.8%). Pour les patients qui ont reçu plus d’un traitement de deuxième ligne (n = 116), la séquence de traitement la plus courante était la splénectomie, suivie par les médicaments immunosuppresseurs (n = 7; 6.0%). Sur les 154 patients évaluables à la fin du suivi, 69 (44.8%) ont obtenu une réponse complète de la numération plaquettaire et 101 (65.5%) une réponse partielle. ConclusionLes médicaments immunosuppresseurs et la splénectomie sont couramment utilisés comme traitements de deuxième intention pour le PTI au Canada. Les choix de traitement et la séquence des traitements sont variables.

Enhanced Responses to Fostamatinib As Second-Line Therapy and in Persistent Immune Thrombocytopenia (ITP) Patients

Enhanced Responses to Fostamatinib As Second-Line Therapy and in Persistent Immune Thrombocytopenia (ITP) Patients

Second-Line Therapy for Immune Thrombocytopenia: Real-World Experience

Background: Immune Thrombocytopenia (ITP) is an autoimmune platelet disorder that can lead to serious morbidity caused by bleeding and therapy-associated toxicities. The sequence of first-line therapies is well-defined, but the sequence of second-line therapies lacks consensus. A description of real-world experience is necessary to understand practice patterns with respect to second-line therapies and identify gaps in care. The objective of this study was to describe the types and chronological sequences of second-line therapies in a large cohort of ITP patients. Methods: This was a retrospective cohort study. The population was derived from the McMaster ITP Registry, a prospective longitudinal registry of patients presenting with thrombocytopenia (platelets &lt;150 × 109/L) to an academic hematology clinic in Hamilton, Canada. Inclusion criteria were: 1) diagnosis of primary or secondary ITP at most recent follow-up; 2) received one or more second-line therapy since initial ITP diagnosis; and 3) ≥6 months of follow up. No exclusions were applied. The sequence of second-line therapies was determined by treatment start dates. For treatments that were administered before enrollment in the registry, the order of treatment was determined by the reported treatment start date. When the start date was not reported, the sequence of treatments was assumed to be the order in which they were mentioned in the medical records. Second-line therapies included: splenectomy; rituximab; danazol; dapsone; thrombopoietin receptor agonists (TPO-RAs): eltrombopag or romiplostim; and immunosuppressants: mycophenolate, cyclosporine, azathioprine or cyclophosphamide. Results: From January 2010 to December 2017, 789 patients with thrombocytopenia were registered in the McMaster ITP Registry. Of those, 204 had ITP and received second-line therapy (57.4% female). Median duration of ITP from the initial presentation to the most recent diagnosis was 9 years (IQR, 4-19). The proportion of patients who received each type of second-line therapy at any time were immunosuppressants (n=106, 52.0%), splenectomy (n=106, 52.0%), TPO-RAs (n=75, 36.8%), danazol (n=73, 35.8%), rituximab (n=67, 32.8%), and dapsone (n=4, 2.0%). Overall, 69 unique treatment sequences were identified. For patients who received one second-line treatment only (n=88), the most common single treatment was splenectomy (n=28, 31.8%), followed by immunosuppressants (n=21, 23.9%) and danazol (n=18, 20.5%) (Figure 1). For patients who received more than one second-line therapy (n=116), the most common treatment sequences were splenectomy followed by immunosuppressants (n=7, 6.0%); immunosuppressants followed by rituximab (n=6, 5.0%), and immunosuppressants followed by danazol (n=5, 4.0%). In patients who received each of these therapies, the last second-line treatments received were TPO-RAs (52/75, 69.3%), immunosuppressants (45/106, 42.5%), rituximab (37/67, 55.2%), splenectomy (36/106, 33.9%), danazol (33/73, 45.2%), and dapsone (1/4, 25%). Conclusion: The types and sequences of second-line therapies for ITP were variable in a large Canadian academic center, where access to certain treatments including TPO-RAs and rituximab is limited. In this setting, splenectomy and immunosuppressant medications were commonly used as early second-line therapies. TPO-RAs were most often the last second-line treatment in the sequence of therapies used. Drug accessibility and other factors related to the choice of second-line therapies require further evaluation. Disclosures Arnold: Bristol-Myers Squibb: Research Funding; Principia: Consultancy; Rigel: Consultancy, Research Funding; Novartis: Honoraria, Research Funding.

Platelet Apoptosis and PAI-1 Content Are Involved in the Procoagulant Profile of Immune Thrombocytopenia Patients Responders to Agonists of Thrombopoietin Receptor.

Background: The treatment goal for patients with immune thrombocytopenia (ITP) is to raise platelet counts to levels that minimize or stop bleeding. Thrombopoietin receptor agonists (TPO-RAs) have been successfully and extensively employed as second-line therapy for ITP. TPO-RAs, however, have a small but significant increase in the risk of thrombosis.Aim: The aim of this study was to elucidate the mechanisms involved in the procoagulant effect of TPO-RAs.Methods: This is a prospective, observational and transversal study. Eighty-two patients with chronic primary ITP, 40 without treatment for at least six months (UT-ITP) and 42 responders to TPO-RA therapy (64.3% with eltrombopag and 35.7 % with romiplostim) were recruited. One hundred and twelve healthy participants were also included.ROTEM® (naTEM test: only recalcification) was performed on platelet rich plasma adjusted to a platelet count of 25 x 109/L. Clotting time (CT, time from start of measurement until 2 mm of amplitude [in seconds], alpha angle, which reflects the rate of fibrin polymerisation (tangent to the curve at 2 mm amplitude [in degrees]), maximum clot firmness, which reflects the maximum tensile strength of the thrombus (MCF, [in mm]) and LI60, which describes the percentage of maximum clot strength present at 60 min (in %), were recorded.Surface exposure of phosphatidylserine (PS), active caspase-3, -8 or -9 and prothrombinase complex binding to platelets were assessed by flow cytometry.Plasma and platelet levels of PAI-1 were determined by ELISA (eBioscience Ltd., Hatfield, United Kingdom). The effect of TPO and romiplostim on PAI-1 content of MEG-01 cells was evaluated by Western blot. Three MEG-01 cell cultures were initiated simultaneously: control without drugs and treated with either TPO (100 ng/mL) or romiplostim (53 μg/mL). Samples were collected at the start and after 24, 48 and 72 hours to determine the PAI-1 content.The statistical analysis was performed using SPSS 9.0 software (SPSS Inc., Chicago, Illinois, USA).Results: The ROTEM® studies showed significant differences in the dynamics of clot formation when comparing the control with ITP samples.There was a delay in clot formation in the UT-ITP group, as observed by a prolonged CT [expressed as median (p25-p75): control: 516 (490- 633) s; UT-ITP: 938 (914-1348) s, p<0.001], and a diminished alpha angle (mean±SD; control: 61.7±5.6 degrees; UT-ITP: 49.2±7.3 degrees, p<0.05). Nevertheless, samples from patients with UT-ITP reached the same MCF as those from healthy controls (control: 45.3±2.4 mm; UT-ITP: 46.9±3.7 mm). On the other hand, patients with ITP undergoing TPO-RA therapy presented an initial clot formation similar to that of the control group [expressed as median (p25-p75): CT, 672 (598-928) s; alpha angle, 55.8±5.8 degrees] but achieved a higher MCF (53.1±4.5 mm, p<0.05) and a reduced clot lysis after 60 min (control: 91.8±4.0%; UT-ITP: 93.7±4.0%, TPO-RA ITP: 97.6±1.7, p<0.05).Higher values of MCF observed with platelets from ITP patients treated with TPO-RAs might be a consequence of their augmented apoptosis signs: platelets from this group exposed more PS than controls and this situation was accompanied by an increased activity of caspases-3,7, -8 and -9 (Figure 1 A and B). Moreover, platelets from ITP patients on treatment with TPO-RAs bound more prothrombinase complex than platelets from UT-ITP patients and healthy controls (Figure 1 C).Reduced clot lysis observed in ITP patients treated with TPO-RA was due, at least in part, to increased plasma and platelet levels of PAI-1 (Table 1).Increase in platelet content of PAI-1 might be the result of the effect of TPO-RAs during megakaryopoiesis since treatments of MEG-01 cells with TPO or romiplostim induced a 3-fold increase in their endogenous PAI-1 content after an incubation period of 48 hs.Conclusion: The patients with ITP undergoing TPO-RAs therapy presented a procoagulant profile due to the formation of a more fibrinolysis-resistant clot because of increased platelet and plasma PAI-1 levels.Moreover, platelets from this group of patients showed more signs of apoptosis that causes a higher exposure of PS and, consequently, a larger surface for the binding of the prothrombinase complex.Work supported by grant from FIS-FEDER PI15/01457. NB holds a Miguel Servet II (FIS-FEDER CP14/00024). [Display omitted] DisclosuresÁlvarez-Roman:SOBI: Consultancy; NovoNordisk: Consultancy; Shire: Consultancy. Jimenez-Yuste:Grifols: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; CSL Behring: Consultancy; Bayer: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding. Butta:FIS-Fondos FEDER: Research Funding.

Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia

BackgroundLaparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication. MethodsA retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 × 109/L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals ≥65 years. ResultsOne hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications. ConclusionLaparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids.

Efficacy and safety of dapsone as second line therapy for adult immune thrombocytopenia: A retrospective study of 42 patients.

Dapsone is recommended as a second line therapy in immune thrombocytopenia (ITP), but is underused because of its potential side effects. The medical charts of 42 ITP patients treated with dapsone (100 mg/day) were retrospectively reviewed in order to assess its efficacy and safety in daily clinical practice. The overall response rate was 54.8% (n = 22, with a complete response in 38.1%) with a median time to response of 29 days (24–41 days). Patients with complete response had shorter disease duration whereas no difference was observed between responders and non-responders regarding age, sex or previous treatments received. Importantly, after dapsone withdrawal, a sustained response was observed in 5 patients, representing 12% of the whole cohort. Twenty percent of patients (n = 8) relapsed on therapy after 8.1 (6.5–13.6) months. Side effects occurred in 31% (n = 13) of patients, and required dapsone withdrawal in 22% (n = 9) or dosage reduction in 10% (n = 4) of the cases. Side effects resolved in all but one case. Overall, these data support dapsone as an interesting second line therapy in ITP, with a good safety and efficacy profile at a low cost.

Risk infection to spare bleeding? The quandary of splenectomy for immune thrombocytopenia.

Risk infection to spare bleeding? The quandary of splenectomy for immune thrombocytopenia.

Long Term Follow up of Patients with Immune Thrombocytopenia Receiving Rituximab

Abstract 4675 Introduction:Rituximab has been used in the management of chronic immune thrombocytopenia (ITP) with promising results. The risk of losing response, however, is yet to be determined with long term follow up. Method:We retrospectively analyzed 32 consecutive patients (20 females, 12 males) with ITP (including 6 patients with secondary ITP) treated with rituximab in two tertiary care hospitals in Oman between May 2006 and May 2011. Response criteria were based on the International Consensus report (Rodeghiero F et al. Blood 2009). Result:The median age at diagnosis was 25 years (range, 4 – 58). Clinical presentation ranged from mild echymosis to more severe central nervous system bleeding. Patients received a median of one line of therapy before rituximab (range, 1–4), including 3 patients who failed splenectomy. Patients received intravenous rituximab using 375 mg/m2 once weekly for 4 weeks. The median time from diagnosis to receiving rituximab was 21 months (range, 1– 177). Only one patient was positive for Hepatitis C virus, but no hepatitis B or HIV positive in this cohort. Anti nuclear antibody was positive in 34% (10/29) of patients. The median hemoglobin and platelet counts at diagnosis were 12 g/dl (range, 5–16) and 11×109/L (range, 1–60) respectively. The median follow up time after rituximab was 26 months (95% confidence interval: 11–40). The overall cumulative response rate was 59% (partial response of 15% and complete response of 44%). The median time to respond was 30 days (Standard error [SE] 49) with a response rate of 44% at 4 weeks (95% Confidence interval: 29–62%). The multivariable Cox model analysis (variables include: age at diagnosis, gender, number of previous therapies and primary vs. secondary) revealed none of the variables included to be statistically significant. The cumulative rate of loss of response was 32% (6/19) with a median time to lose response of 54 months (SE, 0.03). In patients who lost response, the median time to lose response was 17 months (SE, 14). Of the 6 patients who lost response, 4 received a second course of rituximab and all 4 achieved a full response. No major side effects to rituximab were reported during the follow up. Conclusion:Rituximab is an effective and a well tolerated second line therapy for ITP. The response to rituximab can be maintained for a long duration with a high rate of response after retreatment. None of the pretreatment variables studied carried a significant predictive value for response. The study was limited by the small sample size and further larger prospective studies are recommended. Disclosures:Off Label Use: Rituximab was used in our study as a second line for the management of chronic immune thrombocytopenia.

Low anti-HCMV IgG level as a consequence of transient hypogammaglobulinemia in infected premature infants

B-cell depletion with rituximab (RTX) is widely used to treat autoimmune diseases, especially as second-line therapy for immune thrombocytopenia (ITP). The incidence of RTX-induced hypogammaglobulinemia is unknown because of heterogeneous follow-up and confounding factors such as concomitant immunosuppressive treatments in most patients. We describe 3 cases and attempted to determine the incidence of RTX-induced hypogammaglobulinemia by a systematic review of the literature.We retrospectively analyzed 189 ITP patients receiving RTX in 3 referral centers in France and conducted a systematic review of 32 studies (results published 2001–2014) reporting the use of RTX for ITP, particularly searching for symptomatic secondary hypogammaglobulinemia. We also searched for case reports of hypogammaglobulinemia after RTX initiation for ITP.Of the 189 patients, 3 showed symptomatic hypogammaglobulinemia more than 2 years after RTX infusion (initial immunoglobulin level was normal). All 3 presented recurrent severe infections. In 2, the outcome suggested common variable immunodeficiency. In patient 3, the peripheral blood lacked CD19+CD20+ B cells and the bone-marrow B-cell precursor level was impaired. Among 1245 ITP patients in the literature who received RTX for ITP, gammaglobulin level was monitored before and after RTX initiation for 351 (28%). For 192 (55%), dosages were available and we identified 21 patients with secondary hypogammaglobulinemia, usually not symptomatic, 14 of whom had received concomitant dexamethasone. Finally, we found 4 case reports of ITP and symptomatic hypogammaglobulinemia possibly related to RTX according to the authors.This large analysis led us to recommend monitoring serum immunoglobulin level before and repeatedly after RTX initiation for ITP. Physicians should be aware of hypogammaglobulinemia as a rare but severe complication of RTX.