Duration Of Immune Thrombocytopenia Research Articles

Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Risk stratification and outcomes of intracranial hemorrhage in patients with immune thrombocytopenia under 60 years of age

Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296–7.979, P =.012), a platelet count ≤ 15,000/μL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044–2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088–3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360–5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717–15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532–12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.

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

Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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 <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.

PB2253 CHARACTERIZATION OF A POPULATION OF PATIENTS WITH MULTI‐REFRACTORY IMMUNE THROMBOCYTOPENIA: RESPONSE QUALITY AND DURATION WITH SEQUENTIAL THERAPY

Background:Immune Thrombocytopenia (ITP) has a significant impact on the quality of life of patients, particularly in patients that do not respond to several therapeutic lines. In the absence of clear recommendations regarding the best therapeutic sequencing and the lack of robust factors to predict response to treatment, it is relevant to evaluate, in a real‐life context, the efficacy of the different available therapies.Aims:The aim of this study is to evaluate the platelet response after therapy in patients with multi‐refractory ITP.Methods:Retrospective data collection from clinical files of outpatients with multi‐refractory ITP in 4 Portuguese terciary centers, treated at any time with thrombopoietin analogues (TPO‐Ra) until september 30 2018.Results:A total of 104 patients were evaluated, 78.8% with chronic ITP, with a median duration of ITP of 7.5 years (1.0‐58.0). Median age was 53 (2‐86) years old, 11.5% (n = 12) patients were diagnosed in pediatric age, 67.3% (n = 70) were female, and 95.5% (n = 99) have been treated with 3 or more therapeutic lines. Only 1 patient was not treated with first‐line corticosteroid therapy due to acquired immunodeficiency.The overall response rate, defined as platelets>50x109/L for at least 8 weeks, was 36% (n = 90) for corticotherapy, 49% (n = 45) for splenectomy, 22% (n = 23) for rituximab, 59% (n = 89) for eltrombopag, 63% (n = 23) for romiplostin and 12.5% (n = 32) for therapies more rarely used: azathioprine (n = 11), danazol (n = 10), CSA (n = 6), MFF (n = 3) and dapsone (n = 2). The response rates for eltrombopag and romiplostim in splenectomized patients were 48.9% and 22.2%, respectively.The median duration of response to splenectomy was 72.3 months and to rituximab was 6 months. Regarding to TPO‐Ra therapy, the median duration of response was not yet reached in our population, and almost half of patients are still under eltrombopag therapy (n = 41, 41.8%).In 35% of patients under eltrombopag therapy it was possible to suspend it after a median of 102 days, with maintenance of platelet response; in 12 patients on romiplostim, discontinuation of the therapy occurred after a median of 288.5 days, and 10 of these patients switched to eltrombopag.Summary/Conclusion:This retrospective study included a Portuguese patient population followed due to multi‐refractory ITP. The best response rates were obtained with splenectomy and TPO‐Ra and, in this last group, the responses were lower in previously splenectomized patients, which is not according to the literature. Rituximab response rates are lower than the ones expected for an unselected population; one possible explanation is the small number of patients treated and the selection of patients particularly difficult to treat. In 35% of patients treated with eltrombopag, it was possible to maintain response after discontinuation of therapy, as expected. These results should be considered together with the known safety profile of the different therapies and patients preferences. Long‐term prospective assessment remains relevant.

Assessment of Romiplostim Immunogenicity in Adult Patients in Clinical Trials and in a Global Registry

Background: Romiplostim (Nplate®) is a thrombopoietin (TPO) receptor agonist approved for the treatment of adult chronic immune thrombocytopenia (ITP). The formation of antibodies (Abs) against romiplostim may lead to a loss of response, and a theoretical risk exists that an immune response against romiplostim might lead to the formation of Abs that bind both romiplostim and native TPO. We therefore examined Abs against romiplostim and TPO in adult patients (pts) enrolled in clinical trials and in a global postmarketing registry based on spontaneously submitted requests for Ab testing.Methods: The clinical trial population included adult pts (age ≥18 years at screening) with ITP who received ≥1 dose of romiplostim in any of 13 completed romiplostim clinical trials, including phase 1 (n=1), phase 2 (n=3), phase 1/2 (n=1), phase 3 (n=5), and open-label extension (n=3) studies. Duration of romiplostim treatment varied among the trials. The postmarketing global registry population included romiplostim-treated adult pts with ITP who had blood samples sent for Ab testing. Serum samples from the clinical trials and the registry were assessed for romiplostim and TPO binding Abs in a surface plasmon resonance (SPR)-based immunoassay, and samples positive for binding were assessed for neutralizing activity in a cell-based bioassay, as previously described (Jawa et al. Ann Hematol 2010). Pt characteristics were summarized for those who did and did not develop Abs in the clinical trials. Pts in the registry found to have romiplostim neutralizing Abs were to be followed every 3 months for up to 12 months. No formal statistical analyses were conducted.Results: A total of 1046 romiplostim-treated pts from clinical trials were available for analysis. At baseline, 958 pts had romiplostim Ab results: 35 pts (3.7%) were positive for binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 961 pts had romiplostim Ab results: 80 pts (8.3%) were positive for binding Abs and 4 pts (0.4%) were positive for neutralizing Abs, independent of the baseline result.Sixty (6.2%) pts negative for anti-drug Abs at baseline developed romiplostim binding Abs during the clinical trials. Characteristics of the pts who did and did not develop romiplostim binding Abs are presented in Table 1. Development of romiplostim binding Abs was more frequent in pts with ITP duration >3 years at baseline (70.0% vs 57.4%), prior splenectomy (48.3% vs 37.5%), and a history of allergies (21.7% vs 8.4%). Pts who developed Abs also had lower baseline TPO levels (84.8 pg/mL vs 104.6 pg/mL), lower baseline platelet counts (12.5× 109/L vs 20.5 × 109/L), and a higher number of previous ITP treatments (median 3 vs 2).Four of the 60 pts with romiplostim binding Abs developed romiplostim neutralizing Abs after treatment (0.38% of 1046 pts overall; Table 2). The emergence of neutralizing Abs did not appear to be related to romiplostim dose or platelet count. The neutralizing Abs were directed against the peptide component of romiplostim and did not bind native TPO.Pts in the clinical trials were also tested for TPO Abs. At baseline, 956 pts had TPO Ab results: 31 pts (3.2%) were positive for TPO binding Abs and 1 pt (0.1%) was positive for neutralizing Abs. Post-baseline, 960 pts had TPO Ab results: 33 pts (3.4%) were positive for TPO binding Abs and no pts were positive for neutralizing Abs.Of the 184 adult pts in the registry, 9 (4.9%) were positive for binding Abs: 5 were positive for romiplostim binding, 2 for TPO binding, and 2 for romiplostim and TPO binding. No predose Ab results were available for these pts. One pt received romiplostim for 11 months at a dose of 2 µg/kg and then experienced an abrupt fall in platelet count even as romiplostim dose was increased to 10 µg/kg. The pt tested positive for romiplostim binding and neutralizing Abs. Romiplostim was discontinued, and the pt was switched to alternative therapy.Conclusions: An analysis of pts in 13 clinical trials shows that pts with indicators of more severe disease (longer duration of ITP, prior splenectomy, and a higher number of previous ITP treatments) may be at increased risk of developing romiplostim binding Abs. Development of romiplostim neutralizing Abs was uncommon in the clinical trials, and these Abs did not bind native TPO. Data from a postmarketing registry showed that the overall risk of clinically significant immunogenicity following exposure to romiplostim is low. [Display omitted] DisclosuresBarger:Amgen Inc.: Employment, Equity Ownership. Boshier:Sanofi: Other: rents a room to a Sanofi employee; Amgen Inc.: Employment, Equity Ownership. Kim:Amgen Inc.: Employment, Equity Ownership. Mytych:Amgen Inc.: Employment, Equity Ownership. Park:Amgen Inc.: Employment, Equity Ownership. Kuter:Amgen Inc.: Consultancy; Argenx: Consultancy; Rigel: Consultancy, Research Funding; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Principia: Research Funding; Protalex: Research Funding; Pfizer: Consultancy; Bioverativ: Consultancy, Research Funding; ONO: Consultancy; Syntimmune: Consultancy; BMS: Research Funding.

Characteristics, outcome, and response to therapy of multirefractory chronic immune thrombocytopenia

AbstractRefractory immune thrombocytopenia (ITP) was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the risk of significant bleeding events. In this multicenter study, we included 37 patients with multirefractory ITP, defined as no response to splenectomy, rituximab, romiplostim, and eltrombopag. As compared with a historical cohort of 183 ITP patients, matched on the calendar year of ITP diagnosis with a 5:1 ratio, patients with multirefractory ITP were more likely to have secondary ITP (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.31-17.86; P = .018) and monoclonal gammopathy of undetermined significance (OR, 5.94; 95% CI, 1.08-32.48; P = .04). The median duration of ITP before being recognized as multirefractory was 78 months (range, 6-450). The patients showed failure of a median of 10.5 prior treatment lines for ITP (range, 6-15). At the end of follow-up (median, 84 months; range, 12-455), only 1/14 patients achieved response with immunosuppressant therapy alone. By contrast, 7/10 patients achieved response with a combination of immunosuppressant therapy and thrombopoietin-receptor agonists that lasted for a median of 15 months (range, 6-32). Throughout the course of ITP, 5/37 patients died, 3 with ITP (bleeding, n = 2; sepsis n = 1); 15 (40%) had at least 1 bacterial infection and 9 (24%) at least 1 episode of thrombosis. In conclusion, multirefractory ITP was associated with high morbidity and mortality. Combining an immunosuppressant therapy with thrombopoietin-receptor agonists may be a good strategy for management for these patients with severe disease.

Depression in adult patients with primary immune thrombocytopenia

Depression in adult patients with primary immune thrombocytopenia

Gender and duration of disease differentiate responses to rituximab-dexamethasone therapy in adults with immune thrombocytopenia.

Adults often develop chronic immune thrombocytopenia (ITP) for which treatment order is uncertain. Rituximab and three cycles of dexamethasone (4R + 3Dex) improve treatment responses and short-term disease control but long-term outcome is not known. In adults with ITP treated with 4R + 3D, we sought long-term outcome and associated prognostic variables. Forty-nine adults treated at Weill-Cornell received 4R + 3Dex. Their clinical characteristics were reviewed. Duration was median time to treatment failure; Kaplan-Meier estimates were developed. Vbeta Tcell receptor (VBTCR) repertoire was obtained after treatment in 36 patients. Patients were adults with ITP 18-64 years old, median age 37. The 27 females were twice as likely to have an ongoing response to 4R + 3Dex (44.1%) as males (19.6%; P = 0.009). For ITP duration <12 months, 52.7% of patients had continuing responses to 4R + 3Dex compared to 15.3% of patients with diagnosis >12 months (P = 0.02). Females with ITP duration of <12 months had continuing responses in 78.6%, compared to males with <12 months duration of ITP (21.2%). For patients with disease duration <12 months, 67% of females had continuing responses, compared to 31% of males (P = 0.004). Post-treatment polyclonal VBTCR was seen in 9/10 continuing responders (six female, three male) but only 13/26 relapsers/nonresponders (P = 0.068). Durable remissions after treatment with 4R + 3Dex were more frequent in female patients with <12 months of ITP duration and those with polyclonal VBTCR after treatment, emphasizing the roles of duration of disease, gender and T cells in chronic ITP. Differences in pathophysiology of ITP by gender and by duration of ITP require further study. Am. J. Hematol. 91:907-911, 2016. © 2016 Wiley Periodicals, Inc.

Response to TPO-Receptor Agonists: Role of Immature Platelet Fraction and Anti-GP1b

Background: Thrombocytopenia in Immune Thrombocytopenia (ITP) results from a combination of increased platelet destruction and reduced production, both often secondary to anti-platelet antibodies. Absolute immature platelet fraction (A-IPF) is a measure of young reticulated platelets in peripheral blood, and therefore provides an assessment of platelet production. Decreased platelet production in patients with ITP has been addressed by the recently developed Thrombopoietin Receptor Agonists (TPO-RA), which stimulate megakaryopoiesis and thereby, in responders, increase platelet production to a level which overcomes platelet destruction. The majority of ITP patients will respond to these agents, but which ones will respond is not known.Aims: To exploreA) whether baseline A-IPF levels are associated with platelet response to TPO–RA, andB) whether antibodies to platelet glycoproteins 1b or β3 influence the platelet response to TPO-RA.Methods: Platelet counts and A-IPF values were collected from patients treated with TPO-RA (n=91) at Weill Medical College of Cornell University until 2013. All available counts were included, and the median count for each month was determined pre-treatment, and at 1, 2, 3, 4, 5, and 6 months. Patients were divided by whether (n=20) or not (n=71) they often received rescue therapy (i.e. IVIG and/or daily steroids >10mg).The 71 patients who received minimal or no rescue treatment were deemed responders if the average of their six median monthly platelet counts doubled from baseline and was >50x109/L. Based on pretreatment A-IPF, patients were stratified into three cohorts: low (0-25), middle (26-40), and high (41+). Clinical variables such as age, splenectomy status, duration of ITP, and gender were also studied. The 20 “rescue” patients were similarly analyzed.The 84 patients with available sera had their antibody levels measured to GP1b and β3 by Elisa by Dr. Ni. Samples were sent to the lab and analyzed without knowledge of response status or associated A-IPF level. Patients were divided into four categories for analysis of their antiplatelet antibodies: positive for anti-ß3 antibody, positive for anti-GP1b, positive for both, or negative for both.Fisher’s exact, student t-, and chi-square tests were used to analyze differences in response to TPO-RA among patient groups, A-IPF levels, and anti-platelet antibodies.Results:71 Patients with Minimal Rescue TherapyFifty-nine of the 71 patients responded to TPO-RA. There was no significant difference in A-IPF values for responders and non-responders (p=0.95; Figure 1). A significant positive correlation was observed between increase in A-IPF over the 6-month period and response rate to TPO-RA (p=0.009). Age, gender, duration of ITP, and splenectomy status neither correlated with response rate, nor trended with A-IPF cohorts. [Display omitted] 20 Patients with Rescue TherapyFor the 20 patients who often received rescue therapy, low response rates were seen in the low A-IPF cohort and high response rates in the higher A-IPF cohorts. The percent of responders to treatment was higher in patients with chronic ITP than with newly diagnosed and persistent ITP (p= 0.04). Age, gender, and splenectomy status showed no relationship with response to TPO-RA. In comparison with the 71 patient group, the 20 patients presented lower response rates in all groups, with the exception of females.Anti-platelet AntibodiesThere was a weak correlation between A-IPF and anti-GP1b antibody levels (R=0.225), demonstrating that antibodies to GP1b may have a specific impact on platelet production.Patients who did not have detectable antibody to either GP1b or β3 responded better to TPO-RA than patients who tested positive for both Anti-GP1b and Anti-ß3 (p=0.003). The strongest correlation was observed between level of anti-GP1b and response to TPO-RA (p<0.001; Figure 2). [Display omitted] Conclusion:Rather than baseline A-IPF levels or clinical variables, the best predictor of good response to TPO-RA therapy was the absence of anti-GP1b and anti- β3 platelet antibodies, especially anti-GP1b. An explanation for the dominant effect of antibodies to GP1b is that stimulating megakaryopoiesis with TPO-RA would not effect a platelet increase as these antibodies may block proplatelet extension, preventing platelet release into the circulation. This may also explain the effect of anti-GP1b on response to steroids and IVIG. DisclosuresOff Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Bussel:Amgen: Equity Ownership; GSK: Equity Ownership; Amgen: Membership on an entity’s Board of Directors or advisory committees; GSK: Membership on an entity’s Board of Directors or advisory committees; Amgen: Research Funding; GSK: Research Funding; Sysmex: Research Funding.

A Pilot Study to Assess Quality of Life in Older Children and Adolescents with Primary Immune Thrombocytopenia

▪Background: Primary immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired platelet production which may result in severe and chronic, symptomatic thrombocytopenia in a considerable minority of patients. The impact of chronic ITP (cITP) on the health-related quality of life (HRQoL), as it occurs in children, is not well defined.Methods: We administered a validated, age-appropriate HRQoL instrument, the Kids ITP Tools (KIT) (Klaassen, et al. 2007) consisting of 27 questions to assess the HRQoL of older children and adolescents with cITP and the burden it places on their caregivers. Numerical KIT scores, ranging from 0-100 are inversely related to HRQoL. The Platelet Disorder Support Association (PDSA) invited participants (8 to 18 years of age) and their parents to complete an online version of the KIT survey and a background demographic and clinical questionnaire.Results: The survey and questionnaire was completed and returned by 74 children, 168 parents and 90 parents (as proxies for their children) and were evaluable in 70, 155, and 80, respectively. Pediatric participants had male-to-female ratio of 0.98, a mean age and duration of ITP of 12.8 and 5.6 years, respectively. Bleeding symptoms were reported in 97% and drug treatment for ITP in 94%; 44% received an ITP treatment within the last month. Team sports and extracurricular club participation was reported in 42.9% and 54.3%of children, respectively. Twenty percent reported having been bullied. The relationship to being bullied and other determinants of HRQoL were not studied in this pilot study. No significant difference in KIT scores was noted by age, recent treatment or history of bleeding symptoms. The younger cohort (8-12 years), reported a significantly worse HRQoL than the older cohort, aged 12-18 years (p=0.042). In addition, a worse HRQoL was reported by children with ITP < 3 years compared to children with ITP ≥ 3 years (p=0.031), children with > 5 treatment side effects compared to children with ≤ 5 treatment side effects (p=0.010), children with no sports participation compared to children with sports participation (p=0.009). Parents-as-proxy reported a worse HRQoL for children with the shorter duration of ITP (p=0.008), > 5 treatment side effects (p=0.003), co-morbid health conditions* (p=0.009), and no sports participation (p=0.002). Parental burden was reported as worse if their child with ITP was younger (p=0.025), non-Caucasian (p=0.025), had ITP < 3 years (p=0.026), had co-morbidities (p=0.048), or didn’t participate in social clubs (p=0.046). A high degree of correlation, r = 0.8, was noted between the patient and parent-proxy answers. Areas of non-concordance between KIT scores and degree of parental burden included race, number of treatment side effects, and sports or social club participation. The study was limited by potential for ascertainment bias and survey fatigue.C onclusions: This pilot study of the HRQoL in older children and adolescents with cITP showed that the HRQoL results are largely well correlated among the children, parent-proxy and parental burden results. Worse HRQoL was reported in children less than 12 years of age, those having 5 or more side effects to prior ITP treatment, and individuals not participating in sports. The study provides insight to the somewhat unpredictable determinants of parental burden and will facilitate larger cross-sectional HRQoL study of children and adolescents with cITP.*thyroid disease, inflammatory bowel disorders, stomach ulcer, hearing loss, kidney problems, skin disorders, genetic syndromes, asthma, diabetes, anemia, recurrent infections, allergies, seizures, heart conditions DisclosuresKruse:Amgen: Research Funding. Mathias:Platelet Disorder Support Association: Consultancy.

Successful Discontinuation of Eltrombopag after Complete Remission in Patients with Primary Immune Thrombocytopenia

Background: Eltrombopag is effective and safe for treating chronic immune thrombocytopenia (ITP) patients who have not responded to previous therapy. Interestingly, some patients in whom hemostatic platelet counts are achieved with eltrombopag may sustain the platelet response when eltrombopag ceases to be administered. However, the frequency of sustained responses after discontinuing eltrombopag without additional therapy for ITP is largely unknown.Methods: A total of 260 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry were retrospectively evaluated. The study was performed in accordance with the standards of the Helsinki declaration and approved by the Hospital Universitario de Burgos Ethics Committee.Results: The median age was 62 [range, 18–93] years. There were 165 women and 95 men. According to the standard definition, patients were allocated to newly diagnosed (n=29), persistent (n=36) and chronic (n=195) ITP groups. The median time from diagnosis to eltrombopag initiation was 24 [range, 1–480] months. The median number of previous therapies was 3 [range, 0–10], including splenectomy (22%), rituximab (23%) and romiplostim (19%). The initial response rate to eltrombopag was 231/260 (89%), including 77% (n=201) cases of complete remission (platelet count ≥100 x 109/L). The median duration of eltrombopag treatment was 6 [range, 1–54] months.Eltrombopag was discontinued in 80 out of 201 (39.8%) patients who achieved CR. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=33), platelet count >400x109/L (n=29), patient’s request (n=5), aspartate aminotransferase elevation (n=3), diarrhea (n=3), thrombosis (n=3) and other reasons (n=4). For analysis of discontinuation, patients with follow-up < 6 months (n=15), newly diagnosed ITP (n=11) or patients who received concomitant or previous (6 months before) treatments at the start of eltrombopag use (n=5) were excluded. Of the 49 evaluable patients, 22 (45%) had an immediate relapse after stopping eltrombopag. One patient with sustained response after stopping treatment relapsed at 10 months. A total of 26 patients (53%) showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow-up of 9 [range, 6–25] months. These patients were characterized by a median time since ITP diagnosis of 46.5±114.1 months, with 4/26 having ITP <1 year. Eleven patients (42%) were male and their median age was 59 [range, 18-88] years. They had received a median of four previous treatment lines [range: 0–9 lines] and 11 (42%) were splenectomized. The median platelet count before starting eltrombopag was 22 x 109/L and that before eltrombopag withdrawal was 269 x 109/L.The main characteristics (age, gender, duration of ITP, prior anti-ITP lines, prior splenectomy, prior rituximab, prior romiplostim, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 26 patients with sustained response after stopping eltrombopag were compared with those of the 23 patients relapsing after eltrombopag withdrawal. No predictive factors of sustained response after eltrombopag withdrawal could be identified.Conclusion: Platelet response following eltrombopag cessation may be sustained in nearly half of adult patients with primary ITP after CR with eltrombopag. However, reliable markers for predicting which patients will have this response are lacking. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcomes Of Splenectomy-Sparing Therapies For Immune Thrombocytopenia

Background Anti-Rh(D) (Cooper Blood 2002), rituximab (Godeau Blood 2008), and dapsone (Sharma ASH 2006) have been shown to be splenectomy-sparing agents for the treatment of immune thrombocytopenia (ITP). In these studies, patients treated with anti-Rh(D) and rituximab were followed for 2 years; patients were treated with dapsone for 6 to 48 months. Specific Aims To determine long-term outcomes in unsplenectomized patients with ITP treated with anti-Rh(D), rituximab, or dapsone. Methods Institutional Review Board approval was obtained. The charts of 52 consecutive patients with ITP followed in a hematology practice between 07/01/03 and 06/30/13 were reviewed. Response was defined as a platelet count (PLT) &gt; 100,000/µL. Relapse was defined as PLT &lt; 30,000/µL. Results Twenty-one patients have been treated with anti-Rh(D), rituximab, or dapsone. Some patients treated with anti-Rh(D) or rituximab received brief concurrent steroids. For the entire cohort the mean duration of ITP was 3.50 years (y), range 0.008 to 19 y and the mean duration of follow-up was 3.84 y, range 0.10 to 8.81 y. Among 16 patients who received anti-Rh(D), 85% responded to the initial infusion. Among the 10 responders who have had follow-up exceeding 1 year, 4 have had a sustained response following the first infusion (mean follow-up duration 3.35 y, range 2.66 y to 5.98 y; six have relapsed, all have responded to retreatment. Among 7 patients who received rituximab, 71% responded to the initial treatment. All 5 responders have had follow-up exceeding 1 year, among whom 2 have had a sustained response following the first infusion (mean follow-up duration 2.24 y, range 2.19 y to 6.67 y); three have relapsed, all have responded to retreatment. Among 3 patients who received dapsone, 66.7% responded; the response is partial in 1 patient with PLT 50,000/µL (mean follow-up duration 3.94 y, range 0.11 y to 8 y). Toxicities have included: with anti-Rh(D) 1 case each of grade II uterine pain, grade II chills, and grade II non-cardiac chest pain; with rituximab 1 case of grade II back pain. Therapeutic switches have included 2 cases of anti-Rh(D) to rituximab and 1 case each of anti-Rh(D) to rituximab to dapsone, anti-Rh(D) to rituximab to dexamethasone, anti-Rh(D) to romiplostim, and dapsone to rituximab. No patients have undergone splenectomy. Conclusion Anti-Rh(D), rituximab, and dapsone are splenectomy-sparing therapies for ITP over an extended period. For patients treated with anti-Rh(D) or rituximab who relapse, retreatment is effective. Disclosures: Off Label Use: Rituximab and dapsone therapies of ITP.

Safety and Efficacy Of Rituximab In adult's Immune Thrombocytopenia (ITP) : Results After One-Year Of Follow-Up In 252 Patients From The Prospective French ITP-Ritux Registry

Introduction Adults with ITP usually respond to corticosteroids but typically relapse after discontinuation. Rituximab is thought to be an effective off-label second-line treatment but only few prospective data exist about its long-term efficacy and its long-term safety is a matter of concern. The tolerance and particularly the risk of severe infection is a crucial factor for assessing the risk/benefit ratio of this treatment in ITP. Three years ago, we opened a non-interventional prospective registry in France to investigate the safety (primary outcome) and the efficacy of rituximab in off-trials adults with ITP (ClinicalTrials.Gov: NC1101295). Two hundred and fifty two patients were included on a two-year period. A follow-up duration of five-year is planned. We report here the first results after one year of follow-up. Methods The ITP-Ritux registry was set up by the French reference center of adult’s immune cytopenias. Thirty one centers participated to the study. Consecutive patients diagnosed with primary ITP according to the international guidelines (Rodeghiero et al, Blood 2009) who were treated with rituximab were included. Patients with a secondary ITP and those who were previously treated with rituximab were excluded. Response to treatment was assessed according to international guidelines: complete response (CR) was defined by platelet count ³100x109/L and response (R) by a platelet count between 30 and 100x109/L with at least a doubling of the pre-treatment count. The prospective and sequential monitoring of rituximab efficacy and safety was made by using of a standardized electronic case report form. Study nurses visited each center regularly to update the clinical and biological data on the enrolled patients. Results Between July 2010 and July 2012, 252 patients (64% of females) with a mean age of 51±21 (16-97) years were enrolled. The median duration of ITP was 1.3 (0-56) years with 44 patients (17%) with a newly diagnosed ITP, 61 (24%) with persistent ITP and 147 (58%) with chronic ITP at time of rituximab treatment. The median platelet counts at time of ITP diagnosis and rituximab first infusion were respectively 18x109/L (1-100) and 17x109/L (1-186). Patients received a median of 2 treatment lines (range 0-7) before rituximab and 25 (10%) were splenectomized. The standard regimen of 375 mg/m2 weekly rituximab infusions for 4 weeks was administered to 179 patients whereas 73 patients (29%) received a fixed dose of 1000 mg on day 1 and day 15. At time of the present analysis, the median follow-up was 18 months and the one-year response was available in 209 patients. A one-year overall response was observed in 90/209 (43%) patients including a CR in 28% and a R in 15%. Nineteen patients who failed to respond to rituximab were splenectomized during the year following rituximab infusions. Sixty eight adverse events occurred in 47 patients (19%). Rituximab infusions have to be stopped in only 3 patients for severe hypotension, dyspnoea with laryngeal discomfort and reversible serum sickness respectively. Three other patients developed severe adverse event related to rituximab requiring admission in hospital including 1 episode of profound neutropenia while 6 episodes of infections occurred in 2 patients. Seven patients (2.7%) have died during follow-up, 52 to 385 days after rituximab infusions. All patients who died but one aged of 18 were 68 to 98-year old. Only one death could be potentially related to rituximab (enterococcus faecium pulmonary infection), 2 deaths were of unknown origin, other causes were: suicide (n=1), multiple myeloma (n=1) and fatal haemorrhage related to ITP (n=2). We did not observe any episode of progressive multifocal encephalopathy or any other case of opportunistic infection. Discussion and conclusion Our preliminary results based on the first large non-interventional prospective registry of ITP-adults treated with rituximab in the “real life” confirm that this treatment leads overall to 40% of response after one year of follow-up. Safety of rituximab at 1 year appears to be good since severe infections were uncommon and no opportunistic infections were observed. The ongoing monitoring and upcoming analysis with a planned follow-up up to 5-years will provide more data on long-term safety. Disclosures: No relevant conflicts of interest to declare.

Childhood Immune Thrombocytopenia—Who Will Spontaneously Recover?

Although the majority of children with immune thrombocytopenia (ITP) have a short duration of the disease, the very rare but significant complications of the disease often cause fear and anxiety among families of children with ITP. Added to the reduced quality of life (QoL) of those children are restrictions imposed on daily activities to avoid trauma. Treatment decisions in chronic ITP and especially regarding splenectomy are hampered by the inability to predict when recovery will take place. Identification of predictors of recovery would be beneficial for improving treatment decisions and QoL of both children and families. This literature review focuses on clinical parameters and emerging genetic biomarkers for prediction of duration of childhood ITP. Higher recovery rates were found among infants with newly diagnosed ITP. In contrast onset of the disease at adolescence was associated with worse recovery rates. Six clinical features were found to be associated with short duration of disease; the most prominent ones were abrupt onset of bleeding symptoms (<2 weeks) and age at onset ≤ 10 years. Two genetic biomarkers have been suggested as predictors of chronic disease: overexpression of vanin-1 (VNN-1), an oxidative stress sensor, and the Q63R missense variant of the gene encoding the cannabinoid receptor type 2. To be clinically useful each of those predictors requires further validation in larger studies. Genetic biomarkers will potentially offer direct and early prognosis estimation.

Rituximab Combined with 3 Cycles of High Dose Dexamethasone Improves Response in Patients with Newly-Diagnosed, Persistent, and Chronic Immune Thrombocytopenia (ITP)

Abstract 3345 Introduction:Adults with newly-diagnosed ITP usually respond to initial prednisone treatment but typically relapse upon its tapering or discontinuation. Patients with persistent/chronic ITP treated with prednisone have an even lower likelihood of a lasting response. Dexamethasone (Dex) has been reported to have curative effects in newly diagnosed patients. Rituximab (Ritux) is thought to be effective in newly diagnosed patients but only yields a long term response in 20–25% of chronic ITP patients. Recently, newly-diagnosed previously-untreated patients received a single cycle of 4 days of Dex 40 mg/day or 4 infusions of 375mg/m2 Ritux combined with Dex. R+Dex in that study yielded a 63% response at 6 months and 34% at 3 years without additional treatment, which was more effective than Dex alone. Methods:Given the additive activity of these two drugs, 59 patients at Weill-Cornell Medical College with ITP of any duration were treated with 4 infusions of 375mg/m2 rituximab and three 4-day cycles of high-dose dexamethasone at 2-week intervals (R+Dex). Optimal response was assessed after 8 weeks as complete remission (CR, platelet count≥100×109/L) or partial remission (PR, 50–100×109/L). Long term outcome was also assessed and both were related to clinical variables. Data was compared to that of rituximab alone using the previous study from our center (Cooper BJH 2004). AIPF values were gathered prior to treatment until 12 weeks after treatment initiation. Results:All but 5 patients had been previously treated with a median of 2 therapies (range 0–7). Assessing optimal response achieved, 44/59 (74.5%) patients responded, with a CR in 64% and a PR in 10%. Only 1/28 patients with ITP < 1yr relapsed (at 12 months). Duration of ITP less than 24 months (p=0.0426) and being an adult predicted better optimal responses (p=0.0154).Of the original 44 responders, 33/59 patients [74% of responding adults and 77% of responding children] had ongoing responses at last f/u at a median of 14 months without the need for further ITP treatment (Figure). Eleven of the 44 relapsed (25%) including the one at 12 months mentioned above. Two additional patients relapsed who had ITP for 1–2 years prior to R+Dex and the other 8 patients who relapsed had ITP for greater than 3 years, 5 of whom had had ITP for 6+ years.Additionally, 53 of the 59 patients were genotyped for β1-tubulin gene. Of the ten patients with heterozygote genotypes, 9 (90%) responded to combination R+Dex treatment and 32 of the 43 wild type patients responded to treatment (p=0.46). There were no overt differences in the AIPF levels over the first 12 weeks between responders and non-responders. No AIPF differences were seen between the heterozygote and wild type patients for the β1-tubulin gene.In our previous study of rituximab alone, 54% of the 57 adult patients responded to rituximab treatment, compared to 86% of the 36 adult patients who responded to R+Dex treatment. R+Dex responders were found to have a longer duration of lower B cell numbers when compared with responders to rituximab alone, preliminarily demonstrating the additive effect of the 2 medications.Adverse events related to R+Dex generally were mild but one patient was hospitalized with colitis, two others experienced serum sickness reactions and dexamethasone was sometimes difficult to tolerate. Conclusion:R+Dex is active and appears clearly superior to rituximab alone in this single-center, pilot study. Adults and patients who have a shorter duration of ITP (< 1–2 years) fare better but children and those with a longer duration of ITP still have a 1/3 chance of a lasting response. The absence of homozygote β1-tubulin SNP’s in this population made interpretation of its effect difficult. High dose Dex is not always easy to tolerate but helps maintain the count during the treatment course of 32 days. A prospective, randomized trial is planned. [Display omitted] Disclosures:Basciano:Alexion: Consultancy. Ghanima:Roche Pharmaceuticals: Research Funding. Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

Successful Discontinuation of Eltrombopag Treatment in Patients with Chronic ITP

AbstractAbstract 1085 Introduction:Patients with immune thrombocytopenia (ITP) commonly experience platelet increases while under treatment with thrombopoietin-receptor agonists (TPO-RA). Anecdotal evidence suggests certain patients have been able to discontinue TPO-RA and still maintain platelet counts above baseline without additional treatment. This prospective ongoing study was designed to investigate the frequency and characteristics of patients exhibiting sustained responses after electively discontinuing eltrombopag (a TPO-RA) without substituting additional therapy. Methods:Enrolled patients were required to have ITP defined by consensus guidelines (Provan, Blood, 2009) for at least 6 months and must have been taking eltrombopag for a minimum of 4 months prior to starting this observational study. Rescue therapy is permitted once in the first 4 weeks off eltrombopag. The primary response endpoint was prospectively defined as a platelet count of ≥30,000/μl and ≥20,000/μl above initial baseline for 6 months off eltrombopag without intervening treatment (other than rescue). The secondary endpoint was being stably off therapy at 4 weeks after discontinuing eltrombopag. All patients who meet the 2 inclusion criteria (ITP for 6 months and eltrombopag for 4 months) are eligible for the study. Results:Fifteen patients are currently enrolled. Ages range from 3 to 86 years, median 55 years, with 10 females. There are 5 responders of 5 months or more (3 females, 2 males) and 10 non-responders (7 females, 3 males). Four of 5 responders have been off therapy for 6 months or more; the fifth “responder” has been off therapy for 5 months, with platelet counts ≥195,000/μL (figure 1). Responders are aged 19–86 years and have had ITP for 5–34 years; all had been on eltrombopag for > 2 years. Two responders were splenectomized and all had 3 or more prior therapies. One responder and 9 non-responders received rescue treatment in the first 4 weeks. One patient was a responder at 4 weeks, but she lost her response before reaching 6 months off-treatment. Factors not significantly associated with response were: age, duration of ITP, duration of eltrombopag therapy, splenectomy status, number of prior ITP treatments, bleeding history, and platelet count at the time that eltrombopag was discontinued. However, a lower absolute immature platelet fraction (AIPF) value at cessation of eltrombopag was seen in responders (fig 2, p=0.022). AIPF data for 1 non-responder is not available. An AIPF of 900 × 10/μl at the time of discontinuation of eltrombopag exceeds the AIPF of all 5 responders, but also of 3 of 9 non-responders. Conclusions:A substantial fraction of patients with ITP treated with eltrombopag, approximately 1/3, appear able to discontinue eltrombopag treatment and nonetheless maintain an at least adequate platelet count indefinitely (at the very least 6 months). Similar preliminary data has been reported with romiplostim (EHA and ASH abstracts).AIPF values (platelet retics) may better predict a patient's likelihood of successfully stopping therapy than other variables such as those listed above. [Display omitted] [Display omitted] Table 1:Patient DataRespondersBaseline AIPF570670750880890Age (years)5852711926SexMMFFFDuration of ITP (years)55341114Duration of TPO-RA Therapy (years)2.5422.53Number of Prior ITP Treatments (before Eltrombopag)35836Splenectomy Status (yes/no)NNYNYSignficant Bleeding History (yes/no)NNNYNPlatelet Count When Stopping Eltrombopag (×10⋀3/μl)6194182181663Non-RespondersBaseline AIPF8601090650120015006401000x12501450Age (years)5658688622741837510SexFMFFFFMFMFDuration of ITP (years)172318>202.522122127.5Duration of TPO-RA Therapy (years)4432.661.58.832.530.462.33Number of Prior ITP Treatments (before Eltrombopag)47254103726Splenectomy Status (yes/no)NYNNNYNYNNSignficant Bleeding History (yes/no)YYNNYNYYYYPlatelet Count When Stopping Eltrombopag (×10⋀3/μl)12312150101223128257892607 Disclosures:Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

Clinical features and major histocompatibility complex genes as potential susceptibility factors in pediatric immune thrombocytopenia

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder with diverse response rates to treatments that include corticosteroids, intravenous immunoglobulins (IVIG), and splenectomy. The predisposing causes of this autoimmune disorder, one of which is immunogenetic susceptibility, have not been fully determined. We investigated whether clinical features and human leukocyte antigen (HLA) genotypes influence the occurrence, treatment response, and disease duration of childhood ITP in Taiwan. We performed HLA genotyping of 70 Taiwanese children with ITP and of 70 healthy controls and compared the data. Demographic data were also collected and evaluated. The frequencies of heterozygous HLA-A11 and the HLA-Cw1 allele were both significantly decreased in the ITP group (p = 0.0160 and p = 0.0089, respectively), whereas the frequency of heterozygous HLA-DQ5 was significantly increased in the ITP group (p = 0.0057). Patients with HLA-DRB1*11 or -DRB1*15 were more likely to respond poorly to corticosteroids than IVIG (p = 0.0446 and p = 0.0008, respectively). In addition, we observed a positive association between HLA-A11 homozygosity and the development of persistent or chronic ITP [odds ratio (OR) = 6.3165, p = 0.0479]. The presence of HLA-DRB1*08 was, however, negatively correlated with the development of persistent or chronic ITP (OR = 0.1729, p = 0.0657). Children with antecedent of preceding illness (API) and with a younger age of onset were more likely to experience a better treatment response and shorter course of ITP. We suggest that API, age of onset, and particular HLA class I and class II alleles, may be involved in and influence the occurrence and disease duration of childhood ITP, as well as responses to different therapeutic approaches.

Revisiting Splenectomy in Childhood Immune Thrombocytopenic Purpura in the Era of New Therapies: The French Experience

Objective: While splenectomy is the gold standard treatment for refractory primary immune thrombocytopenia (ITP) in adult, its place remains debated in children. The French Rare Disease Plan provided us the opportunity to conduct a collaborative study of the efficiency and tolerance of this procedure in childhood ITP. Patients and methods: A retrospective study was conducted in France in order to identify children with ITP treated with splenectomy during a 9-year period. A total of 78 children were included. Data from the ongoing CEREVANCE national cohort of childhood auto-immune cytopenia in 30 units were reviewed and completed by a direct contact with the referent physicians. International terminology for response definition was used. Relapsefree survival was assessed by the Kaplan-Meier method. Results: The median ages at ITP diagnosis and splenectomy were 9.6 and 12.4 years respectively. The median duration of ITP before splenectomy was 24 months (1-162); 62 children had chronic ITP. The median number of treatment lines before splenectomy was 2 (1-7). Laparoscopy was used in 81% of cases. Four children underwent immediate surgical complications. With a median follow-up of 41 months, complete remission (CR) was maintained at the latest news in 84% of children. CR was obtained in 77% of cases with intra-splenic platelets destruction, and in no case with non-splenic destruction (p=0.11). Using a very strict definition for relapse, the 5-year relapse-free survival was 51% [IC95% 37-64]. No death or overwhelming sepsis was reported. Conclusions: In this national study with a long term follow up, the excellent benefit/risk ratio of splenectomy for refractory ITP confirms that in skilled and concerted teams, the procedure is still at the forefront of curative treatments. Isotopic evaluation is of value but other prognostic factors for CR are to be determined. Lifelong survey of potential infectious and thrombotic risk at adult age has to be coordinated by the referring physician. The place for other therapeutic options, in order to postpone as late as possible the splenectomy in childhood ITP is now to be determined.