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Primary immune thrombocytopenia is an autoimmune disorder characterized by increased platelet destruction and insufficient platelet production without another identified underlying disorder. Splenectomy may alter responsiveness to treatment and/or increase the risk of thrombosis, infection, and pulmonary hypertension. The analysis herein evaluated the safety and efficacy of the thrombopoietin receptor agonist romiplostim in splenectomized and nonsplenectomized adults with primary immune thrombocytopenia. Data were pooled across 13 completed clinical studies in adults with immune thrombocytopenia from 2002-2014. Adverse event rates were adjusted for time of exposure. Results were considered different when 95% confidence intervals were non-overlapping. Safety was analyzed for 1111 patients (395 splenectomized; 716 nonsplenectomized) who received romiplostim or control (placebo or standard of care). At baseline, splenectomized patients had a longer median duration of immune thrombocytopenia and a lower median platelet count, as well as a higher proportion with >3 prior immune thrombocytopenia treatments versus nonsplenectomized patients. In each treatment group, splenectomized patients used rescue medications more often than nonsplenectomized patients. Platelet response rates (≥50×10 9 /L) for romiplostim were 82% (310/376) for splenectomized and 91% (592/648) for nonsplenectomized patients ( P <0.001 by Cochran-Mantel-Haenszel test). Platelet responses were stable over time in both subgroups. Exposure-adjusted adverse event rates were higher for control versus romiplostim for both splenectomized (1857 versus 1226 per 100 patient-years) and nonsplenectomized patients (1052 versus 852 per 100 patient-years). In conclusion, responses to romiplostim were seen in both splenectomized and nonsplenectomized patients, and romiplostim was not associated with an increase in the risk of adverse events in splenectomized patients. clinicaltrials.gov Identifier: 00111475(A)(B), 00117143, 00305435, 01143038, 00102323, 00102336, 00415532, 00603642, 00508820, 00907478, 00116688, and 00440037 ., (Copyright© 2017 Ferrata Storti Foundation.)

Adults with newly diagnosed or persistent immunothrombocytopenia frequently relapse upon tapering steroids; adults and children with chronic disease have an even lower likelihood of lasting response. In adults with newly-diagnosed immunothrombocytopenia, two studies showed that dexamethasone 40 mg/day × four days and 4 rituximab infusions were superior to dexamethasone alone. Studies have also shown three cycles of dexamethasone are better than one and patients with persistent/chronic immunothrombocytopenia respond less well to either dexamethasone or rituximab. Therefore, 375 mg/m(2) × 4 rituximab was combined with three 4-day cycles of 28 mg/m(2) (max. 40 mg) dexamethasone at 2-week intervals and explored in 67 ITP patients. Best long-term response was assessed as complete (platelet count ≥ 100 × 10(9)/L) or partial (50-99 × 10(9)/L). Only 5 patients had not been previously treated. Fifty achieved complete (n=43, 64%) or partial (n=7, 10%) responses. Thirty-five of 50 responders maintained treatment-free platelet counts over 50 × 10(9)/L at a median 17 months (range 4-67) projecting 44% event-free survival. Duration of immunothrombocytopenia less than 24 months, achieving complete responses, and being female were associated with better long-term response (P<0.01). Adverse events were generally mild-moderate, but 3 patients developed serum sickness and 2 colitis; there were no sequelae. Dexamethasone could be difficult to tolerate. Fourteen patients became hypogammaglobulinemic and half had increased frequency of minor infections; 9 of 12 evaluable patients recovered their IgG levels. Rituximab combined with three cycles of dexamethasone provides apparently better results to reported findings with rituximab alone, dexamethasone alone, or the combination with one cycle of dexamethasone. The results suggest medical cure may be achievable in immunothrombocytopenia, especially in women and in patients within two years of diagnosis. (clinicaltrials.gov identifier:02050581)., (Copyright© Ferrata Storti Foundation.)

The treatment of choice in steroid-resistant immune thrombocytopenia is still controversial due to the recent advent of new drugs (anti-CD20 antibodies and thrombopoietin mimetics) that have encouraged a generalized tendency to delay splenectomy. Consequently, it is extremely importance to define the efficacy and safety of splenectomy in the long term. We retrospectively analyzed the data of 233 patients affected by immune thrombocytopenia who underwent splenectomy between 1959 and 2001 in 6 European hematologic institutions and who have now a minimum follow up of ten years from surgery. Of the 233 patients, 180 (77%) achieved a complete response and 26 (11%) a response. Sixty-eight of 206 (33%) responsive patients relapsed, mostly (75%) within four years from first response. In 92 patients (39.5%), further treatment was required after splenectomy that was effective in 76 cases (83%). In 138 patients (59%), response was maintained free of any treatment at last contact. No significant association between baseline characteristics and likelihood of stable response was found. Overall, 73 (31%) and 58 (25%) patients experienced at least one infectious or hemorrhagic complication, which was fatal in 2 and 3 patients, respectively. A stable response to splenectomy was associated with a lower rate of infections (P=0.004) and hemorrhages (P<0.0001). Thrombosis developed in 18 patients (8%) and was fatal in 4. Splenectomy achieved a long-term stable response in approximately 60% of cases. Complications mainly affected non-responding patients and were fatal in a minority.

Autoimmune thrombocytopenia (AITP) is a disorder due to specific platelet auto-antibodies directed against platelet surface glycoproteins. AITP in adults is usually chronic, idiopathic and frequently refractory to conventional treatments. Myelo- and immuno-suppressive chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation is an experimental approach for severe chronic refractory AITP. We report a case of a woman with AITP, refractory to the conventional therapy, submitted to T-cell-depleted autologous PBSC transplantation, which obtained long term stable response on platelet count. We deem that the positive outcome of our patient depends on T-cells depletion of the graft, which reduces autoreactive T clones.

Background and Objectives: Splenectomy is the most effective treatment for patients with severe autoimmune thrombocytopenia (AITP) who do not have a spontaneous or drug- induced remission. However, this treatment has some short and long term risks. There is no consensus on the indications and optimal timing of splenectomy, since it is unknown up to which time from onset of symptoms a remission can be expected without splenectomy., Design and Methods: We studied the incidence of complete or partial remissions in a cohort of 114 adult patients (68 women, 46 men, median age 49.8 years, interquartile range 28.3-68.4) with severe AITP (platelet count < 20x10(9)/L at diagnosis) using Kaplan Meier analysis. Patients who underwent splenectomy during the observation period were censored at the time of splenectomy., Results: The probability of a complete remission was 61% and that of at least a partial remission was 86% at 5 years. The incidence of complete remission was highest within the first 6 months (30%), but increased up to 53% between 6 months and 3 years after diagnosis. The probability of a remission was not related to age, gender, or the presence or absence of platelet antibodies, but was higher in patients with an acute onset of symptoms in comparison to those with an insidious onset (p = 0.0003). The chance of a late remission was higher in patients with an insidious onset of disease., Interpretation and Conclusions: These data indicate that splenectomy may be delayed for up to 3 years, in particular in those patients whose AITP has had an insidious onset.

Background and Objectives: Immune thrombocytopenic purpura (ITP) is an acquired autoimmune disease characterized by platelet destruction. Glucocorticoids are the first-choice treatment, resulting in a complete (CR) or partial (PR) response in 70-80% of cases. In most cases, however, response is transient or glucocorticoid-dependent. For these and for selected patients with acute refractory ITP, splenectomy may produce a good response (CR+PR) in about 60-80% of cases. We report here the long-term outcome of a large cohort of ITP splenectomized patients., Design and Methods: We retrospectively analyzed the data on 402 patients (137 males, 265 females) who underwent splenectomy for ITP between 1959 and 2002 in 22 different Hematology Centers., Results: Seventy-nine of the 345 (23%) responsive patients relapsed, in most cases (80%) within 48 months from splenectomy. Sixty-eight out of these 79 patients (86%) were then treated with a good response in 46/68 (68%) cases. Fifty-four of the 57 patients refractory to splenectomy and were treated, after the surgery, with a good response in 27/54 (50%) cases. Infection and thrombosis did not significantly weigh upon the outcome of the patients. Only three patients died of hemorrhage during follow-up. By multivariate analysis, the number of therapies before (p<0.01) and higher peak post-splenectomy platelet count (p<0.00001) were predictive of a favorable response to splenectomy, whereas only higher post-splenectomy peak platelet count (p<0.001) was predictive of relapse., Interpretation and Conclusions: This study shows that splenectomy is a safe procedure and effective in approximately two thirds of patients with chronic ITP. Further studies are required to establish whether surgery-sparing treatments of chronic ITP, such as high-dose dexamethasone, anti-D and anti-CD20 immunoglobulins, have similar or even superior efficacy, risk and cost ratios compared to splenectomy.

Background and Objectives: Splenectomy is the treatment of choice in the majority of patients affected by idiopathic thrombocytopenic purpura refractory to corticosteroid therapy, but it is not free from early and late complications. As the available literature does not seem to contain any precise indications concerning possible factors predicting the response to splenectomy, the aim of this retrospective study of 65 splenectomized patients was to attempt to identify potentially predictive clinical or laboratory parameters., Design and Methods: For the purposes of statistical analysis, the patients were divided into two groups: the first included those with a complete (platelets > 100x10(9)/L) or partial response (platelets 50-100 x10(9)/L) to splenectomy; the second, the non-responders (platelets < 50x10(9)/L). The non-parametric tests were based on the Kruskal-Wallis method for independent samples, and the independent samples were compared using the Chi-square test according to Pearson., Results: Univariate analysis did not reveal any significant correlation between successful splenectomy and age, sex, platelet count at diagnosis, anti-platelets antibody positivity, the site of platelet sequestration, the time between diagnosis and surgery, or the response to high intravenous immunoglobulin doses. However, the probability of success was greater in the patients with a complete or partial pre-operative response to steroid therapy (p<0.05)., Interpretation and Conclusions: The factor most frequently associated with the success of splenectomy is the site of autologous platelet sequestration. Our study did not identify any clinical or laboratory parameter clearly predictive of post-splenectomy cure other than a transient response to steroid treatment. This finding needs further confirmation in larger patient populations.

Background: All patients with idiopathic thrombocytopenic purpura (ITP), diagnosed in our Department between June 1970 and December 1989, have been analyzed to evaluate the efficacy of treatment, incidence of spontaneous remission and see whether or not there are some parameters that may be indicative of the clinical outcome of these patients., Patients and Methods: A total of 93 children and 397 adults have been evaluated. Response to treatment was any increase in platelet count to above 30 x 10(9)/1, when the platelet count was < 20 x 10(9)/l, or any doubling of the basal platelet count otherwise. Remission was defined as any platelet count higher than 100 x 10(9)/l lasting for 3 months or longer without treatment. For duration of the response and remission, the last check-up with a favorable platelet count was considered or the midpoint between the last favorable check-up and relapse., Results and Conclusions: In children, short-term responses to prednisone were obtained in 78% of acute patients and 67% of chronic patients, while stable remissions or long-term responses were found in 49% and 17% (p = 0.01). In adults, a short term response to prednisone was obtained in 71% of acute and in 72% of chronic patients, while stable remissions or long-term responses in 30% and 5% (p = 0.000003). In 40/45 children (89%), splenectomy induced a stable remission or a long-term response, while in adults, remissions or a long-term responses were achieved in 100/133 (75%) (p = 0.003). Age below 40 was found to be a significant determinant of a better response (p = 0.0013). Of the 92 evaluable adult patients with borderline thrombocytopenia, 8 developed a severe thrombocytopenia (9%). Spontaneous remissions or spontaneous rises to safe levels of platelet counts were recorded in 9% of adult cases presenting with severe thrombocytopenia: among refractory patients, spontaneous remission occurred significantly more frequently in younger patients (p = 0.003). An overall rate of 19% of adult patients continue to need therapy or have become refractory to any treatment. Among these cases, 7 died from cerebral hemorrhage, 6/7 were older than 50 years. Thus, the overall crude rate of thrombocytopenia-related death for our series of patients was 1.8%.

Background: The best treatment for patients with idiopathic thrombocytopenic purpura (ITP) who are refractory to or have contraindications for splenectomy and corticosteroid remains uncertain. We report here our experience with vinca alkaloids (VA), azathioprine (Azp) and danazol in 33 such patients (6 M/27 F), median age 66 (23-83)., Patients: Group A (n = 19), Group B (n = 11), Group C (n = 17) patients were treated with VA, Azp and danazol. Fourteen patients were given more than one immunosuppressor agent. Sixteen patients were given 2 mg/week bolus infusions of vincristine (Vcr), while weekly slow infusions of vinblastine (Vnb, 0.1 mg/kg), for 2-4 weeks, were administered to the remaining 3 cases of Group A. Azp was administered at a daily dose of 150 mg for a median duration of 6 months. Danazol was administered at a median daily dose of 400 mg (400-800 mg), for a median length of 5 months. Response was defined as any increase of platelet count to higher than 30 x 10(9)/l, when platelet count was < 20 x 10(9)/l or any doubling of the basal platelet count otherwise. Remission, any increase of platelet count to higher than 100 x 10(9)/l lasting for 3 months or longer without therapy., Results and Conclusions: In Group A, there was a response rate of 63%, with 2 remissions (10%). All responses were observed after the first infusion. Two additional patients, who responded transitorily to VA, went into spontaneous remission 19 and 51 months after the last infusion of VA. In Group B, the response rate was 45%, with 1 remission (9%). The response was never observed before one month. One additional patient went into spontaneous remission 60 months after stopping Azp. In Group C, the response rate was 56% with 2 remissions (12%); 2 patients relapsed while on therapy, 4 continue to require therapy and 1 died from a stroke while on therapy. Four patients in Group A and two in Group B discontinued the therapy because of severe side effects. Danazol was generally well tolerated but for one patient was interrupted after only 5 days because of severe dyspepsia. In conclusion, the clinical usefulness of VA and Azp is very limited and burdened by severe side-effects. Danazol seems to be safer but no more effective and its long-term toxicity is not known. There were two hemorrhagic deaths in this series of patients.

Background and Methods: Splenectomy is still a mainstay in the treatment of idiopathic thrombocytopenic purpura (ITP). Although the risk of fulminant sepsis after splenectomy in children and in adults has been known for a long time, the true prevalence of fulminant sepsis in adults splenectomized for ITP has still not been well established, despite many anecdotal reports. In this paper we have tried to estimate this risk by reviewing the available literature and by analyzing a large cohort of adults splenectomized for ITP at our Institute since 1970., Results: Two cases of fulminant sepsis (a 21-year-old man and a 24-year-old woman) were traced in a group of 133 splenectomized adults, with a crude incidence of 1.5% or, equivalently, of 0.17 cases per 100 patient-years. No case of sepsis occurred in a control group of 323 non splenectomized ITP adults. This estimation seems sufficiently precise for the large population analyzed and the duration and completeness of follow-up (1,126 patient-years, mean 101 months, 2 patients lost from follow-up), and it is in agreement with the estimations yielded by a literature review (1.8%)., Conclusions: The risk of fulminant sepsis seems to be a real hazard in adults splenectomized for ITP, and a conservative approach in recommending splenectomy seems advisable. Antipneumococcal vaccination should also be recommended.

We describe our experience with ascorbic acid in the treatment of chronic refractory ITP. Nine patients, 5 males and 4 females aged 27-74 years, 4 of whom were previously splenectomized, received the drug at a daily dose of 2 grams. After 2-12 months (median 4) of treatment, a partial response was observed in only one patient, while no response was registered in the other eight. Our data, analyzed together with those of the literature, allow us to conclude that ascorbic acid may not be considered a drug of interest in the treatment of chronic refractory ITP.