Methylprednisolone Versus Intravenous Immunoglobulin As Initial Therapy In Adult Immune Thrombocytopenia

Abstract Background Both intravenous methylprednisolone (methyl-Pd) and intravenous immunoglobulin (IVIg) have been used as standard initial therapies in adult patients with immune thrombocytopenia (ITP). Nonetheless, few studies have addressed whether there are differences in clinical efficacy between these two treatments. In this study, we compared platelet responses, toxicities, and bleeding-related mortality associated with these two treatments in adult ITP. Patients and Methods Adult patients newly diagnosed with ITP, with platelet counts of less than 20,000/mL, were prospectively enrolled. Patients with comorbidities such as diabetes and uncontrolled cardiovascular disorders and who were pregnant were excluded. Patients who entered the study between 1993 and 2002 received intravenous methyl-Pd therapy (10 mg/kg/day for 3 days) followed by oral Pd (1 mg/kg/day). Patients who entered the study between 2003 and 2008 received IVIg (400 mg/kg/day for 5 days) together with oral Pd (1 mg/kg/day). After 6 weeks, the prednisolone began to be tapered in both arms. Early response and maintenance of response were assessed at 7 days and 6 months after treatment, respectively, based on the outcome criteria proposed by an international working group (Blood 2009). Results Of 87 patients enrolled, 77 (88.5%) were eligible for analysis. Initial platelet counts did not differ between the two groups. Early responses occurred in 30 of 39 patients (76.9%) receiving methyl-Pd versus 33 of 38 patients (86.6%) receiving IVIg (p = 0.187). Maintenance of response was observed in 28 patients (71.8%) in the methyl-Pd arm and 23 patients (60.5%) in the IVIg arm (p = 0.187). The time to a complete response in the IVIg arm (6 days; range, 1–35 days) was shorter than that in the methyl-Pd arm (13.5 days; range, 2–29 days) (p = 0.002). Side effects were mild and tolerable in both arms. Five years after treatment initiation, 5 patients (12.8%) and 7 patients (18.4%) were still under salvage treatment in the methyl-Pd and IVIg arms, respectively. During a median follow-up of 98 months (range, 33-228 months) in the methyl-Pd arm and 71 months (range, 52-180 months) in the IVIg arm, 19 patients (48.7%) and 18 patients (47.4%) patients required one or more salvage treatments, respectively (p = 0.906). No bleeding-related death was observed in either group during the follow-up period. Conclusion These results indicate that neither the early response rate nor the long-term outcome differs between methyl-Pd and IVIg treatments. IVIg, however, more rapidly induces a complete response than methyl-Pd. Disclosures: No relevant conflicts of interest to declare.

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Thyroid Disorder-Related Immune Thrombocytopenia: Clinical and Laboratory Characteristics

Blood ◽

10.1182/blood.v112.11.4561.4561 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4561-4561 ◽

Cited By ~ 1

Author(s):

Eric M. Cheung ◽

Rahul Naik ◽

Michael Keng ◽

Howard A. Liebman

Keyword(s):

Immune Thrombocytopenia ◽

Response To Therapy ◽

Overt Hypothyroidism ◽

Published Data ◽

Thyroid Disorders ◽

Thyroid Disorder ◽

Term Outcome ◽

Long Term Outcome ◽

Platelet Counts

Abstract Thyroid disorders have been associated with immune thrombocytopenia. However, there is little published data regarding the clinical and laboratory manifestations of patients with hyper- and hypothyroidism-related thrombocytopenia (Th-ITP) compared with those with euthyroid chronic immune thrombocytopenia (E-ITP). We reviewed the medical records for 135 patients who fulfilled American Society of Hematology criteria for chronic ITP. Results: Of the 135 patients, 71 (52.6%) were screened for thyroid disorders. Of these 71 patients, 17 (23.9%) were diagnosed with thyroid disorders, including 5 (29.4%) with overt hyperthyroidism, 5 (29.4%) with subclinical hyperthyroidism, 4 (23.5%) with overt hypothyroidism, and 3 (17.6%) with subclinical hypothyroidism. Four patients were diagnosed with thyroid disorders prior to their diagnosis of immune thrombocytopenia while 13 were diagnosed after. The duration of ITP follow-up was similar for the E-ITP (46.1 mo; range: 1– 333 mo) and Th-ITP patients (50.5 mo; range: 1– 173 mo). Age (49.9 yrs for Th-ITP vs. 45.9 for E-ITP), gender (82.3% females for Th-ITP vs. 70.3% for E-ITP), initial platelet counts (17.27 × 109/L for Th-ITP vs. 18.87 × 109/L for E-ITP), and initial bleeding manifestations (64.7% for Th-ITP vs. 66% for E-ITP) were not significantly different between the two groups. Significantly fewer Th-ITP than E-ITP patients had platelet counts <50k at diagnosis (76.5% vs. 85.6%, p = 0.021). There was a trend for Th-ITP to have platelet counts <50k at the end of follow-up (23.5% vs. 8.5%, p = 0.064), despite having a similar duration of follow-up and receiving a similar numbers of individual therapies (2.82 vs. 3.13). However, fewer Th-ITP patients underwent splenectomy (17.65% vs. 38.98%, p = 0.087). Lupus anticoagulant and anti-cardiolipin antibodies were more common in Th-ITP than E-ITP patients, although this difference was not statistically significant (40% vs. 26.2%; p=0.086). Conclusions: Thyroid disorders are commonly observed in patients with immune thrombocytopenia, but do not appear to significantly affect the response to therapy or long-term outcome in ITP patients.

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Characteristics of Sarcoidosis-Associated Immune Thrombocytopenia: a Consecutive Study of 20 Cases.

Blood ◽

10.1182/blood.v114.22.2407.2407 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2407-2407

Author(s):

Matthieu Mahévas ◽

Laurent Chiche ◽

Medhi Khellaf ◽

Yurdagu Uzunhan ◽

Anne-Sophie Morin ◽

...

Keyword(s):

Platelet Count ◽

Partial Response ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Respir Crit ◽

Standard Form ◽

Complete Response ◽

Biological Data ◽

Long Term Outcome

Abstract Abstract 2407 Poster Board II-384 Introduction: Although sarcoidosis is far from being a classical cause of secondary-immune thrombocytopenic purpura (ITP), isolated thrombocytopenia may occur during the course of the disease. To better assess the main characteristics and outcome of patients with a sarcoidosis-associated ITP, a survey was initiated throughout the French study group on sarcoidosis and the national referral center for adult's immune cytopenias. The data of the 20 first cases are reported. Patients and Methods: To be included, all patients had to fulfil the following criteria: 1) Definite diagnosis of sarcoidosis according to the standard international criteria (Am J Respir Crit Care Med 1999; 736-55) and 2) Presence of an immune thrombocytopenia according to the ASH criteria twith platelet count below 100 × 109/L on at least two separate occasions 2 weeks. Drug-induced thrombocytopenia were excluded as well as patients with a hypogammaglobulinemia suggesting a underlying common variable immunodeficiency (CVI) and thrombocytopenia related to hypersplenism. All clinical and biological data were reviewed and analyzed by the same investigator by using a standard form. A complete response (CR) was defined as sustained (> 3months) platelet count > 100 × 109/L with at least a twofold increase for baseline. A partial response (PR) was defined as a platelet count 30×109/L or more and at least twice the initial value. Results: Twenty patients (50% men) were included. Median age at ITP diagnosis was 37.5 years (21 to 83) and median age at sarcoidosis diagnosis was 36 yrs (10 to 83). In 4 patients, ITP preceded the diagnosis of sarcoidosis (median: 67.5 months; 15 to 153). In 11 patients (55%), ITP occurred in the course of prior diagnosed sarcoidosis with a median of 48 mths (6 to 216), and concomitantly with the diagnosis of sarcoidosis in 5 patients (25%). In 13 patients (65%), an active localization of sarcoidosis was present at the diagnosis of ITP. Median platelet count at onset was 11×109/L (3 to 90) and nadir platelet count was 10×109/L (1 to 60). Seven patients (35%) had severe (mucosal) bleeding manifestations and a bleeding score ≥ 8 (described by Khellaf et al). Regarding sarcoidosis, during the follow up, 17 patients (85%) had thoracic involvement, and an extra-thoracic involvement was found in 14 patients (70%) including: eye (n=7), liver (n=5), sinus (n=4), peripheral lymph nodes (n=4), skin (n=3), salivary gland (n=2), spleen (n=1) and kidney (n=1). Nineteen out of the 20 patients were treated specifically for their secondary ITP. After the first line therapy (prednisone at 1mg/kg/day for at least 3 consecutive weeks in all patients associated with IVIg in 10 patients), 12/19 (63%) patients achieved a complete response (CR), 6 a partial response (PR) (32%) and only 1 patient failed to respond. The course of ITP was chronic in 4 patients, among them 2 underwent splenectomy and achieved a CR and 2 were treated with Rituximab (375mg/m2, 4 infusions) and achieved a PR at one year. After a median follow up of 70 months (12 to142), 18 patients (90%) were in CR and 2 in PR with chronic ITP. Eight patients were in remission off therapy whereas 12 patients (60%) were still on corticosteroids at time of analysis with a median dose of 10mg/day (5 to 30). During the follow-up period, 11 patients (55%) had a relapse or flare of sarcoidosis (intra thoracic in 5 patients, extra-thoracic in 6 patients). In 2 patients, a simultaneous relapse of both sarcoidoisis and associated-ITP was observed. Comments: Our preliminary data suggest that the association of sarcoidosis and ITP is not fortuitous and that sarcoidosis should be considered as a potential cause of secondary ITP. ITP in this setting is frequently initially severe and symptomatic and therefore requiring treatment. The overall response rate to treatments commonly used in primary ITP is however good and the long term outcome is favorable suggesting that patients with sarcoidosis-associated ITP should be managed as patients with primary ITP. In contrast, relapse of sarcoidosis is frequent and frequently affect extra-thoracic sites. That a majority of the patients had an active and/or relapsing sarcoidosis during the course of ITP suggests that granuloma may be a predisposing condition for triggering autoimmunity and especially ITP as observed in some cases of CVI-associated immune thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

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.

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Bortezomib Induction Followed by ASCT in Patients with Multiple Myeloma: Achievement of Response After Induction and Achieving CR Post-ASCT Are Both Important Prognostic Markers

Blood ◽

10.1182/blood.v118.21.1866.1866 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1866-1866

Author(s):

Min Kyoung Kim ◽

Chang-Ki Min ◽

Myung Soo Hyun ◽

Kihyun Kim ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Conflicts Of Interest ◽

Induction Treatment ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival

Abstract Abstract 1866 Background: In multiple myeloma (MM), the association between the response to induction before autologous stem cell transplantation (ASCT) and long-term outcome is less clear but the situation may change with the introduction of novel agents. We therefore assessed the clinical relevance of response of bortezomib induction treatment or post-ASCT response for patients who received bortezomib-combined induction chemotherapy followed by ASCT. Methods: We retrospectively assessed 183 MM patients who received bortezomib-containing induction therapy (BTZ-IT) followed by ASCT in 24 institutions throughout Korea between 2003 and 2010. Records of these patients were reviewed using the Korean Myeloma Registry database (www.myeloma.or.kr). Each institution was requested to reconfirm the data using additional case report forms. Patients who had overt MM based on International Myeloma Working Group diagnostic criteria were selected. Results: One-hundred seventy eight patients were eligible. Their median age was 56 years (range, 28–69 years) and 96 (53.9%) were male. Forty nine (27.5%) received bortezomib as front-line therapy and 129 (72.5%) as second-line treatment. All patients underwent ASCT and 22 (12.4%) were treated with tandem ASCT. Ninety-seven (54.5%) patients were treated with maintenance therapy after ASCT. After BTZ-IT, the response rates in this selected series of patients were 37.6% CR, 12.4% VGPR, 41.0% PR, 7.3% SD and 1.7% PD (Figure 1A, 1B, 1C); the corresponding post-ASCT rates were 69.2% CR, 14.0% VGPR, 11.0% PR, 2.9% SD and 2.9% PD. At a median follow-up of 46.6 months, the 3-year overall survival (OS) and event-free survival (EFS) rates were 70.0% and 31.9%, respectively. Multivariate analysis showed that factors independently predictive of OS and EFS included achievement of BTZ-IT response °Ã PR (P=0.025 and P=0.014, respectively) and the treatment with maintenance therapy (P=0.048 and P=0.001, respectively). Post-ASCT CR vs. °Â VGPR was also an independent prognostic factor for OS and EFS (P=0.0001 and P=0.002, respectively). Conclusion: At least PR to BTZ-IT and CR after ASCT were predictive of survival. These findings suggest that patients who responded to BTZ-IT may benefit from ASCT due to an enhanced quality of response. Maintenance therapy can also affect patient outcomes. Disclosures: No relevant conflicts of interest to declare.

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A Prospective Multicenter Single-Arm Study of Low-Dose Decitabine in Adult Patients with Immune Thrombocytopenia

Blood ◽

10.1182/blood.v128.22.3744.3744 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3744-3744

Author(s):

Hai Zhou ◽

Ping Qin ◽

Chenglu Yuan ◽

Haiyan Zhang ◽

Zhencheng Wang ◽

...

Keyword(s):

Adverse Events ◽

Intravenous Immunoglobulin ◽

Immune Thrombocytopenia ◽

Low Dose ◽

Conflicts Of Interest ◽

End Points ◽

Thrombopoietin Receptor Agonists ◽

Receptor Agonists ◽

Thrombopoietin Receptor

Abstract Introduction: Approximately 30% of patients with immune thrombocytopenia (ITP) fail to respond to the first- and/or second-line treatments (corticosteroids, intravenous immunoglobulin, rituximab, splenectomy, and thrombopoietin-receptor agonists). For those patients, the management is challenging. Decitabine (DAC), a demethylating agent with a dual mechanism of action: the demethylating effect leading to cell differentiation at low dose and cytotoxic activity leading to cell death at high concentration, has been used in the management of myelodysplastic syndrome (MDS) with a considerable platelet response during the past decade. Recent studies proved that low-dose DAC was sufficient to show a therapeutic effect with no obvious cytotoxicity. Our previous and other studies have demonstrated that low-dose DAC could promote megakaryocyte maturation and platelet production. These findings suggest a possible therapeutic role of low-dose DAC in the management of ITP. We hereby present the preliminary results of a prospective, multicenter, open-labeled study evaluating the efficacy and safety of low-dose DAC for ITP patients. Methods: ITP patients, who failed to respond to corticosteroids, intravenous immunoglobulin, rituximab, and/or thrombopoietin-receptor agonists from 9 centers, were enrolled in the study. The study protocol was approved by the ethics committee on medical research of each participating site. All patients provided written informed consent in accordance with the Declaration of Helsinki. DAC was given intravenously at 3.5mg/m2 for 3 days/cycle for 3 cycles with a 4-week interval between cycles. The primary end points were complete response (CR), response (R), overall response (OR). All the criteria were consistent with the standardization of terminology, definitions and outcome criteria in immune thrombocytopenia proposed by the international working group (RodeghieroF, et al. Blood, 2009, 113:2386-2393). Secondary end points were bleeding scores, time to response (TTR), duration of response and adverse events. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events, version3.0. This clinical trial was registered at http://clinicaltrials.gov as NCT 01568333. Results: A total of 20 ITP patients were recruited. The clinical characteristics were shown in Table 1. At the end of the 12th week of the initial treatment, CR was achieved in 1 patient (5%) and R was achieved in 9 patients (45%). The OR rate was 50%. During the follow-up period, 1 patient initially stabilized at R and subsequently improved to CR at the 20th week. Therefore, CR, R and OR rates were 10% (2/20), 40% (8/20) and 50% (10/20), respectively. In patients who achieved CR and R, the median (range) TTR was 22 days (8-38 days). The median (range) follow-up time was 24 weeks (13-40 weeks). The platelet counts of patients who achieved CR and R were shown in Figure 1. The follow-up of our study is in progress. Adverse events were observed in 2 patients, one had nausea and the other was mild fever. No adverse events exceeded grade 1. Conclusion: Although the sample size is small, with a relatively short follow-up period limited by now, our study suggests that low-dose DAC is effective and safe in the management of ITP patients. Disclosures No relevant conflicts of interest to declare.

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Long-term outcome of extratemporal epilepsy surgery among 154 adult patients

Journal of Neurosurgery ◽

10.3171/jns/2008/108/4/0676 ◽

2008 ◽

Vol 108 (4) ◽

pp. 676-686 ◽

Cited By ~ 58

Author(s):

Alaa Eldin Elsharkawy ◽

Friedrich Behne ◽

Falk Oppel ◽

Heinz Pannek ◽

Reinhard Schulz ◽

...

Keyword(s):

Epilepsy Surgery ◽

Cox Regression ◽

Adult Patients ◽

Class I ◽

Seizure Outcome ◽

Term Outcome ◽

Long Term Outcome ◽

Factors Associated

Object The goal of this study was to evaluate the long-term outcome of patients who underwent extratemporal epilepsy surgery and to assess preoperative prognostic factors associated with seizure outcome. Methods This retrospective study included 154 consecutive adult patients who underwent epilepsy surgery at Bethel Epilepsy Centre, Bielefeld, Germany between 1991 and 2001. Seizure outcome was categorized based on the modified Engel classification. Survival statistics were calculated using Kaplan–Meier curves, life tables, and Cox regression models to evaluate the risk factors associated with outcomes. Results Sixty-one patients (39.6%) underwent frontal resections, 68 (44.1%) had posterior cortex resections, 15 (9.7%) multilobar resections, 6 (3.9%) parietal resections, and 4 (2.6%) occipital resections. The probability of an Engel Class I outcome for the overall patient group was 55.8% (95% confidence interval [CI] 52–58% at 0.5 years), 54.5% (95% CI 50–58%) at 1 year, and 51.1% (95% CI 48–54%) at 14 years. If a patient was in Class I at 2 years postoperatively, the probability of remaining in Class I for 14 years postoperatively was 88% (95% CI 78–98%). Factors predictive of poor long-term outcome after surgery were previous surgery (p = 0.04), tonic–clonic seizures (p = 0.02), and the presence of an auditory aura (p = 0.03). Factors predictive of good long-term outcome were surgery within 5 years after onset (p = 0.015) and preoperative invasive monitoring (p = 0.002). Conclusions Extratemporal epilepsy surgery is effective according to findings on long-term follow-up. The outcome at the first 2-year follow-up visit is a reliable predictor of long-term Engel Class I postoperative outcome.

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Thymic-Derived Tolerizing Dendritic Cells Are up-Regulated upon Treatment with Intravenous Immunoglobulin or Splenectomy in a Murine Model of Immune Thrombocytopenia

Blood ◽

10.1182/blood.v126.23.2251.2251 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2251-2251 ◽

Cited By ~ 1

Author(s):

Rick Kapur ◽

Rukhsana Aslam ◽

Edwin R. Speck ◽

Michael Kim ◽

Anne Zufferey ◽

...

Keyword(s):

Dendritic Cells ◽

Intravenous Immunoglobulin ◽

Murine Model ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Scid Mice ◽

Ivig Treatment ◽

High Dose ◽

Platelet Counts ◽

Inflammatory State

Abstract Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by low platelet counts. ITP has a complex pathogenesis, in which both anti-platelet antibodies as well as T cells have been shown to be important. Initial management of newly diagnosed ITP may be either watchful waiting or pharmacologic intervention, such as glucocorticoids or Intravenous Immunoglobulin (IVIg), a blood product consisting of polyclonal immunoglobulin G (IgG) derived from thousands of donors. Second-line therapy may include dexamethasone, high-dose methylprednisolone, rituximab, thrombopoietin (TPO)-receptor agonists, or splenectomy. The working mechanism of IVIg is actively under investigation and is still a matter of debate, as various different working mechanisms have been suggested. One of them is that IVIg may shift the balance from a pro- to anti-inflammatory state through immunomodulating the activity of dendritic cells (DCs). To gain more insights into the role of DCs in ITP, upon IVIg treatment or splenectomy, we analyzed DC subsets in a murine model of ITP, which features both the antibody and T cell mediated thrombocytopenia. Severe combined immunodeficient (SCID) mice were administrated 4x104 splenocytes from CD61 (GPIIIa) knockout mice immunized against CD61 (or naïve control splenocytes) and the mice were treated with or without 1 g/kg IVIg twice a week. Also the same type of splenocytes were transferred into splenectomized SCID mice. Weekly platelet counts were assessed and after 4 weeks the mice were sacrificed and spleen and thymuses were harvested. Splenocytes and thymocytes were isolated and examined by flow cytometry for cross-presenting (XCR1+) and non-presenting tolerizing (SIRP alpha+) DCs. Without IVIg or splenectomy, both splenic DC subset numbers correlated positively with platelet counts and both the thymic DC subset numbers correlated negatively with platelet counts, indicating thymic retention of DC in a setting of thrombocytopenia. Interestingly, splenectomized SCID mice, apart from increased platelet counts, demonstrated a complete reversal of the DC pattern in the thymus, as thymic DC subsets correlated positively with platelet counts in splenectomized mice. Upon IVIg treatment, apart from a general increase in platelet counts, the splenic tolerizing DCs significantly increased in numbers. Moreover, the thymic retention of tolerizing DCs and thus the negative correlation with platelet counts (R2: 0.46, p<0.05) was fully abrogated upon IVIg treatment (R2: 0.02, NS). Overall, our results indicate that both splenectomy as well as IVIg treatment can immunomodulate thymic tolerizing DCs significantly, in a murine model of ITP. Disclosures No relevant conflicts of interest to declare.

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Increased FVIII and Anti-Phospholipid Antibodies Do Not Modify the Clinical Course of Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood.v124.21.5013.5013 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5013-5013

Author(s):

Meet Kumar ◽

Maitryee Bhattyacharyya ◽

Shyamali Datta

Keyword(s):

Platelet Count ◽

Lupus Anticoagulant ◽

Immune Thrombocytopenia ◽

Clinical Course ◽

Conflicts Of Interest ◽

Age Groups ◽

Platelet Counts ◽

Bleeding Score ◽

Chronic Immune Thrombocytopenia

Abstract INTRODUCTION: Immune thrombocytopenia is a heterogenous disease with majority patients having a mild bleeding phenotype and one-fourth being asymptomatic. Bleeding episodes are usually seen in patients with platelet counts typically <30,000/cumm. There is no study till date to identify patients with platelet count <30,000/cumm and at high risk for bleeding. Although patients who harbor anti phospholipid antibodies have a higher risk of arterial and venous thrombosis, it is not known whether presence of acquired thrombophilia modifies the clinical course of bleeding in low platelet count ITP patients. We evaluated the role of FVIII and lupus anticoagulant in modifying the clinical course of such patients. MATERIALS AND METHODS: Patients of all age groups with persistent and chronic immune thrombocytopenia were eligible for study enrolment. Patients with acute ITP and secondary ITP were excluded. Eligible patients were evaluated with baseline parameters, ITP bleeding score (ITP-BAT, version 1.0 by IWG on ITP) at baseline and then at every visit and FVIII and lupus anticoagulant at baseline and repeat at six months.Patients were called for monthly scheduled visits if platelet counts were >30,000/cummand more frequently at lower platelet counts. Patients with any evidence of underlying infection or raised c-reactive protein and procalcitonin were deferred evaluation.All patients were treated as per institutional protocol to avoid treatment bias. Patients were followed up for one year. We finally calculated the average bleeding scores of all patients at different platelet counts (for eg. average of skin, mucosal and organ bleeding scores of all patients that had platelet counts <10,000/cumm, 10-30,000/cumm etc) and analysed it with FVIII and anti-phospholipid antibody levels. RESULTS: A total of 45 patients were enrolled with M:F=1:3.2. Median age of patients is 28years (3-72 years). Two patients were excluded (both progressed to SLE) and another two were lost to follow-up. Median duration from ITP diagnosis to study enrolment was 62.4months (8-590 months). Median follow-up of all patients was 14.2 months (13.2-16.4 months). Nine patients had persistent and 32 patients had chronic ITP. ITP-BAT could differentiate intensity of bleeding at different platelet counts by means of bleeding scores (Table 1). Correlation of bleeding scores with prothrombotic markers could not establish a disease course modifying relationship between the two (Table 2). CONCLUSION: Presence of high FVIII and anti phosphoilipid antibodies donot modify the bleeding risks in patients with ITP and low platelet counts. Table 1Platelet count (x109/cumm)Total episodesAverage bleeding scoreP value<1014S2.4 M1.4 O0 0.00210-3015S1.4 M0.9 O030-6018S0.3 M0.1 O0>600S0 M0 O0 Table 2 Platelet count <10,000/cumm Platelet count 10-30,000/cumm N Av BS P= N Av BS P= FVIII>150 5 S2.5M1.1O0 0.02 6 S1.1M0.8O0 0.1 FVIII<150 9 S2M0.7O0 11 S1.4M0.6O0 LA1:LA2>2 1 S2.2M1.5O0 0.03 S1.1M0.8O0 0.2 LA1:LA2<1 12 S2.6M1.2O0 S1.2M0.6O0 Table 3 Platelet count 30-60,000/cumm Av BS P= FVIII>150 4 S0.9M0.1O0 0.2 FVIII<150 11 S0.3M0.1O0 LA1:LA2>2 Nil LA1:LA2<1 9 S1.1M0.4O0 Disclosures No relevant conflicts of interest to declare.

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Long Term Results of Stanford V Regimen and Highly Active Antiretroviral Therapy (HAART) In 59 Patients (pts) with HD and HIV Infection (HD-HIV)

Blood ◽

10.1182/blood.v116.21.4827.4827 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4827-4827

Author(s):

Michele Spina ◽

Jean Gabarre ◽

Salvatrice Mancuso ◽

Alessandro Re ◽

Clara Schiantarelli ◽

...

Keyword(s):

Highly Active Antiretroviral Therapy ◽

Conflicts Of Interest ◽

Prognostic Score ◽

Disease Free Survival ◽

Long Term Results ◽

Term Outcome ◽

Long Term Outcome ◽

Free Survival

Abstract Abstract 4827 Background: The introduction of HAART has significantly improved the outcome of pts with HD-HIV. However there are no data on the long term follow-up of HD-HIV pts treated with conventional chemotherapy (CT) regimens. In 2002, we reported the results of a prospective phase II study with the intensive 12-week CT with adjuvant radiotherapy (Stanford V) and concomitant HAART in 59 pts (Spina et al. Blood 2002;100:1984-1988). Methods: To analyze the long term outcome of patients included in the Stanford V and HAART protocol. Results: The median follow-up is 67months (range 3–156 months The 5-yr overall survival (OS), freedom from progression (FFP), disease free survival and event free survival are 54%, 52%, 60% and 37%, respectively. The 5-year OS is significantly different in pts with an international prognostic score (IPS) >2 in comparison to that of pts with an IPS <3 (84% vs 36%, p= 0.0005). Similarly, the percentages of FFP at 5 years in these groups are 72% and 45% (p= 0.03). Conclusions: Our data confirm the long term efficacy of Stanford V regimen in combination with HAART in HD-HIV. However, Stanford V is significantly less effective in pts with IPS>2 and therefore new strategies be tested in this setting. Supported by AIRC and ISS grants. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Follow up of Children with Apalstic Anemia Treated with Immunosuppressive Therapy.

Blood ◽

10.1182/blood.v108.11.997.997 ◽

2006 ◽

Vol 108 (11) ◽

pp. 997-997

Author(s):

Bunchoo Pongtanakul ◽

Prabodh K. Das ◽

Yigal Dror

Keyword(s):

Partial Response ◽

Immunosuppressive Therapy ◽

Late Complication ◽

Complete Response ◽

Late Complications ◽

Term Outcome ◽

Long Term Outcome ◽

Long Term Follow Up

Abstract Background: Immunosuppressive therapy (IST) is the alternative first line treatment in children with aplastic anemia (AA) who have no HLA match siblings available. The long-term outcome of patients with AA who survive after IST is unknown. We evaluated outcomes of children with AA treated with IST at long-term follow up. Methods: we retrospectively reviewed the hospital records of children with AA from 1984 to 2004, treated at our institution with horse-derived antithymocyte globulin (hATG) 160 mg/Kg over 4 days, short course of prednisone and cyclosporine (CS). Results: Forty two patients were treated with IST (25 boys, 18 girls). The median age at diagnosis was 8.5 years. Twenty nine (69%), eight (19%) and five (12%) patients were diagnosed with severe, very severe, and moderate AA, respectively. Nine patients (21%) had hepatitis associated AA. Twenty seven patients (64%) received one course of ATG and fifteen (36%) received 2 courses (8 received 2 courses of hATG and 7 received 1 course hATG and 1 course rabbit derived ATG). Eleven patients (26%) required G-CSF. Median follow up time was 53.3 months (range 3–244 months). Twenty six patients (62%) had a complete response (CR), eight (19%) had a partial response (PR) and eight (19%) had no response (NR). Two patients relapsed after one course of IST and needed a second course of IST and both of them had a partial response. Median time to discontinuation of CS was 13 months. Nine patients (21%) died (7 with NR and 2 with PR) and 33 patients (79%) are alive. Two patients developed myelodysplastic syndrome (MDS) 21 and 19 months post IST; both received long-term G-CSF (18 and 14 months) and had PR after 2 courses of IST. Five of 33 patients (15%) who survived had significant hypertension after CS was discontinued and one required continuous antihypertensive medication. Conclusion: The results of this study shows promising response in children with AA treated with IST. Hypertension and MDS are late complication. Longer follow up in these patients is warranted to definite the accurate rates of the late complications and risk factors.

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