Chronic Refractory Immune Thrombocytopenic Purpura Research Articles

Refractory chronic immune thrombocytopenic purpura in a child with acute lymphoblastic leukemia

Immune thrombocytopenic purpura (ITP) has been associated with several hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas and chronic lymphocytic leukemia, but it is rare in children with acute lymphoblastic leukemia (ALL). Here, we report a 7-year-old girl with chronic ITP during early intensive phase of chemotherapy for ALL. She underwent splenectomy because thrombocytopenia had persisted even after treatment with intravenous immunoglobulin (IVIG), steroids, vincristine, rituximab, and anti-D antibody. After splenectomy, her platelet count had recovered, and maintenance therapy could be resumed with a support of IVIG. To our knowledge, this is the first child case of chronic ITP during chemotherapy for ALL and splenectomy was effective in this patient.

Romiplostim in chronic immune thrombocytopenic purpura

Background: Immune thrombocytopenic purpura (ITP) is characterized by platelet deficiency due to platelet destruction and/or inadequate production. Initial therapy consists of corticosteroids or intravenous immunoglobulin (IVIg). Patients with chronic refractory disease might undergo splenectomy. Although there is no treatment of choice in those who do not respond to splenectomy, immunosuppressive agents are typically prescribed. Romiplostim is the first available drug in a recently developed class of agents that work through stimulation of the thrombopoietin (TPO) receptor (c-Mpl) to increase platelet production. Objective: The aim of this report was to review the mechanism of action, pharmacology, clinical activity, and adverse events associated with the use of romiplostim for the treatment of thrombocytopenia in patients with chronic ITP. Methods: MEDLINE, Google Scholar, International Pharmaceutical Abstracts, and Web of Science were searched for English-only clinical trials and reviews (publication dates: 2000-June 1, 2009; key terms: romiplostim, Nplate, ITP, and idiopathic and immune thrombocytopenic purpura). Abstracts from the 2000–2008 meetings of the American Society of Hematology and references from relevant articles were reviewed. Results: A total of 6 studies were included. Romiplostim is the first marketed agent developed to directly stimulate the bone marrow to produce platelets. Produced in Escherichia coli using recombinant DNA technology, it is an Fc-peptide fusion protein. It works intracellularly in a manner similar to that of the naturally occurring TPO to activate the transcriptional pathways, leading to increased platelet production via stimulation of the c-Mpl receptor. Romiplostim was approved by the US Food and Drug Administration for the treatment of chronic ITP primarily based on the findings from 2 multicenter, randomized, placebocontrolled, parallel-group studies in 125 adult patients with chronic ITP and an insufficient response to corticosteroids, IVIg, and/or splenectomy. The most common prior treatments were corticosteroids (94%) and IVIg (80%). Sixty-three patients (50%) were splenectomized a median of 6.6 years earlier. Baseline platelet counts were <30 × 10 9 cells/L. The initial dose of romiplostim was 1 μg/kg/wk SC, with adjustments to maintain platelet counts between 50 and 200 × 10 9 cells/L. The primary end point was a durable platelet response (≥50 × 10 9 cells/L for ≥6 of the last 8 weeks of treatment). The proportion of patients in whom a durable platelet response was achieved was significantly greater with romiplostim than with placebo (49% vs 2%, respectively; P < 0.001). Overall platelet responses (durable plus transient) were achieved in 83% (69/83) with romiplostim and 7% (3/42) with placebo ( P < 0.001). An interim report of findings from an ongoing extension study found that response was maintained for up to 156 weeks (median, 69 weeks) with romiplostim. The most common adverse events were headache (37%), nasopharyngitis (32%), contusion (30%), epistaxis (30%), fatigue (30%), arthralgia (25%), and diarrhea (25%). Conclusions: Based on the findings from this review, romiplostim administration has been associated with a durable platelet response in these patients with refractory chronic ITP. Romiplostim has been found to be generally well tolerated.

Renal Transplantation and Idiopathic Thrombocytopenic Purpura: Two Case Reports

Kidney transplantation has rarely been performed in patients with immune thrombocytopenic purpura (ITP). We present two cases of kidney recipients from unrelated donors in women who had prior chronic refractory ITP. Their immunosuppression included induction therapy with antithymocyte globulin (ATG) and maintenance treatment with cyclosporine and prednisone. Kidney transplantations were safely performed without any complication. The platelet count of our patients increased gradually after the surgery, and maintenance with cyclosporine, mycophenolate mofetil, and prednisolone allowed graft function and satisfactory hemostasis. During the 3- and 8-year follow-up periods in our recipients, graft function was well maintained. We speculated that immunosuppressive agents, especially cyclosporine, may result in safe platelet counts and resolve thrombocytopenia in cases with refractory ITP prior to transplantation.

Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk

AbstractTo determine whether inhibition of Syk would be useful in FcγR-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, mouse models were used to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic. Thus, phase 2 clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Doses were increased until a persistent response was seen, toxicity occurred, or 175 mg twice daily was reached. Eight patients achieved persistent responses with platelet counts greater than 50 × 109/L (50 000 mm3) on more than 67% (actually 95%) of their study visits, including 3 who had not persistently responded to thrombopoietic agents. Four others had nonsustained responses. Mean peak platelet count exceeded 100 × 109/L (100 000 mm3) in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis. In conclusion, inhibition of Syk was an efficacious means of increasing and maintaining the platelet count in half the patients with chronic refractory ITP. (ClinicalTrials.gov, no. NCT00706342).

Can rituximab replace splenectomy in immune thrombocytopenic purpura?

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by premature platelet destruction. Standard practice is to initiate treatment with corticosteroids, followed by splenectomy. Most published literature for responses from rituximab is in patients with chronic refractory ITP, who have failed multiple prior treatments, including splenectomy. We therefore decided to analyze our patient population with ITP who had been treated with rituximab, mainly as a second line treatment regimen prior to splenectomy. We performed a retrospective chart review of patients with a diagnosis of ITP who had been treated with rituximab between January 2001 and December 2006 at our institution. 18/29 patients (62%) had a CR, 2/29 (7%) patients had a PR, representing an overall response rate of 69%. The average time to response was 5 weeks and all patients have maintained their response for more than 12 months after treatment with rituximab. Our study shows higher CR, comparable overall response rates, but with a longer duration of response when compared to the published literature.

Severe chronic refractory immune thrombocytopenic purpura during childhood: A survey of physician management

Physician attitudes regarding management of children with severe chronic immune thrombocytopenic purpura (ITP) have not been recently characterized. We designed a survey of members of the American Society of Pediatric Hematology-Oncology (ASPHO) that described a 5-year-old female with ITP for 1 year who was unresponsive to steroids, IVIG, and anti-D immune globulin and having frequent epistaxis causing interference with her daily activities. A 13-item questionnaire evaluated physician decision-making in this setting. Two hundred and ninety-seven surveys (35% response rate) were returned, and 295 were evaluable. Thirty-three percent of respondents stated that they would recommend splenectomy for such a child. Of those who would not recommend splenectomy, 67% reported that they would instead treat with rituximab. If initial drug therapy failed, 47% would proceed with splenectomy. Those who reported treating with rituximab initially were more likely to recommend splenectomy following failure than those who preferred other drug therapy (P < 0.0001). Physician management of patients with chronic ITP is diverse. With the advent of new treatments such as rituximab and thrombopoetic agents it is critically important to compare their cost, adverse effects and efficacy with splenectomy in order to optimally guide treatment practices.

The effect of anti‐CD40 ligand in immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is mediated by antiplatelet autoantibodies possibly involving CD40:CD40L co-stimulation. Two humanized anti-CD40L monoclonal antibodies, hu5c8 and IDEC-131, were evaluated in 46 patients with chronic refractory ITP. Fifteen patients were treated with 20 mg/kg of hu5c8: four (27%) had complete responses (CR) and two (13%) had partial responses (PR). Three responders to hu5c8 were successfully retreated with IDEC-131, demonstrating its efficacy. Thirty-one subsequent patients were treated with 5-20 mg/kg per infusion of IDEC-131: five (16%) responded (one CR and four PR). The 24% (11/46) overall response rate demonstrates the potential role of CD40-CD40L in the pathogenesis of ITP.

The use of vinca alkaloids in preparation for splenectomy of corticosteroid refractory chronic immune thrombocytopenic purpura patients

Administration of vinca alkaloids (VA) to chronic corticosteroid refractory immune thrombocytopenia (ITP) patients results in a temporary increase of platelet count. The aim of the study was to evaluate the efficacy of vinca alkaloids in preparing adult corticosteroid refractory chronic ITP patients for splenectomy as well as to compare the costs of this method with costs of applying intravenous immunoglobulins. The study included 12 chronic ITP patients refractory to corticosteroids applied for 3-144 months. The patients were prepared for splenectomy with average 3.0 (from 1 to 4) 2-h intravenous infusions of vinca alkaloids at 7 day intervals. In eight patients, vincristin was used in a total dose of 6 mg (2 mg per infusion), in two patients, vinblastin was used in total dose of 30 mg (10 mg per infusion), and in two patients, vincristin and vinblastin infusions were administered alternatively. In nine of the 12 treated patients (75%) the platelet count increased to > or = 80 x 10(9)/l, which allowed safe splenectomy. Three patients unreactive to VA treatment were prepared for splenectomy with intravenous gammaglobulin infusions. Splenectomy was performed in 12 patients, in eight with laparoscopic method, in four with classic method. No complications during surgical intervention were observed. In none of the VA treated patients was myelosupression or liver or/and kidney dysfunction observed. Splenectomy resulted in normalization of platelet count in all patients after operation and in six of nine patients followed up for 10 months (on the average). Matching of VA costs with treatment efficacy and comparison with similar costs for intravenous immunoglobulin treatment revealed many fold lower costs of the former method.

Rituximab Use in Children - A Single Center Experience.

Treatment of children with chronic refractory ITP often results in significant morbidity and current therapies induce remission in fewer than half of children with chronic ITP. Rituximab is a humanized mouse monoclonal antibody against the B cell antigen CD20 that results in the prolonged depletion of B cells. CD20 is relatively selectively expressed on pre-B and mature B cells and may selectively treat antibody-mediated disorders. Among the lymphomas that occur in children, diffuse large cell NHL (DLCL) and Burkitt's lymphoma both express high levels of CD20. Data from adult clinical trials demonstrated that rituximab is active against B-cell low-grade lymphomas, particularly follicular center cell lymphoma, and is also active against diffuse large cell lymphoma. Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, prednisone (CHOP) chemotherapy, with no substantial increase in toxicity. This study examined the efficacy and safety of rituximab in children with chronic immune thrombocytopenic purpura (ITP) and Burkitt's lymphoma. It was a retrospective analysis of all children who received one or more courses of Rituximab in Pediatric Hemato-Oncology unit at Sir Ganga Ram Hospital from January 2005 to January 2006, who met the criteria of minimum follow up of 6 months. Five children age ranging from 3 yr to 11 years received 18 courses of rituximab during the study period. Three patients had chronic ITP (mean duration 20 months) non-responsive to IVIG, prednisolone, cyclosporin etc. Baseline platelet count were 10,000–15000/mm3. Rituximab was tried in an effort to avoid splenectomy. Each patient received 375-mg/m2 dose per course weekly for 4 weeks except one patients who could afford only 2 courses. First patient had response with platelets > 100000/mm3 for 8 months after which they again dropped to 15000/mm3. In other 2 cases sustained response has been seen with platelets >l00000/mm3 till date after a follow up of more than 12 months. Fourth patient had developed ITP during treatment of Precursor B cell Acute lymphoblastic leukemia (ALL) and had no response to steroids and IVIG. He responded after 4 courses of weekly rituximab and has maintained his platelets >50,000 except during chemotherapy blocks with follow up of 10 months. Now he is in maintenance phase of treatment for ALL. Fifth patient had abdominal Burkitt's lymphoma resected but had residual local mass. Bone marrow and CSF were negative. Child was treated as per MCP842 protocol for B cell lymphoma with 4 courses of chemotherapy and Rituximab. Rituximab was given 24 hr prior to start of chemotherapy in each course. Residual tumor cleared after 2 courses of chemotherapy and Rituximab. Child is in remission for 12 months after finishing chemotherapy. In regard to side effects, one patient of chronic ITP developed hypotension and drowsiness 15 min after start of infusion during 1st course which improved after stopping infusion but later it was restarted with no problems and tolerated following 3 courses well. However this same patient developed white matter changes on MRI head done for headache 12 months in follow up. She was also treated with cyclosporin in past and had no neurological problems. Patient with Burkitt's lymphoma developed late onset asymptomatic neutropenia 5 weeks after last course and recovered in following 3 weeks. Rituximab has good efficacy in cases of chronic ITP and Burkitt's lymphoma. However patients should be monitored for acute reactions, late onset neutropenia and long-term effect on brain with white matter changes.

Anti-D Immunglobulin in the Treatment of Childhood Chronic Idiopathic Thrombocytopenic Purpura.

Chronic idiopathic (immune) thrombocytopenic purpura (ITP) develops in approximately 20% of children with acute ITP. The therapies for chronic refractory ITP include splenectomy, steroids, intravenous immunoglobulin (Ig), anti-D Ig, monoclonal antibodies, danazol, chemotherapy, plasma exchange, and others. We report five 5 RhD-positive, pediatric, non-splenectomized patients with chronic immune thrombocytopenic purpura (ITP), treated with anti-D. Patients were refractory to steroids and high dose intravenous immunoglobulin (IVIG). The mean age of the patients was 10.5 years, duration of thrombocytopenia was more than 6 months, and the median platelet count was 6x 10(9)/l. Patients received a single intravenous dose of 75 microg/kg anti-D, and were monitored for response to treatment and adverse events. Complete blood cell and renal function tests were assessed at baseline and 1, 7, 14 and 28 days after infusion. By 24 hours after treatment two of patients had achieved a platelet count>20 x 10(9)/l. Mild headache, fever, or chills occurred in one patients and ameliorated with prednisone and acetaminophen premedication. None of the patients had more than 0.5 gm/dl fall in the hemoglobin level and renal dysfunction following anti-D infusion by day 1,7, 14, 28. A single 75 microg/kg dose of anti-D may increase the platelet count in some children with chronic resistant immune thrombocytopenic purpura with an acceptable safety profile. It is a valuable, safe, well tolerated, and cheap alternative to conventional chronic ITP treatments in selected non-splenectomized patients.

A case of systemic lupus erythematosus expressing intractable thrombocytopenia remedied effectively by intermittent and continuous administrations of a small amount of immune globulin

We describe a case where intermittent and continuous administrations of a small amount of immune globulin were effective in the treatment of refractory chronic immune thrombocytopenic purpura by systemic lupus erythematosus (SLE). Steroid pulse therapy and cyclophosphamide pulse therapy were considered for thrombopenia. However, the patient had compressed fracture of the lumbar vertebrae due to osteoporosis and right external malleolus ulcer with complications of infection. Therefore, high-dose intravenous immune globulin (IVIG) therapy (400 mg/kg daily for 5 consecutive days) was administered. Then, as a maintenance therapy, a small amount of 400 mg/kg for 1 day (400 mg/kg monthly) was given in an intermittent and continuous manner, which resulted in improvement of thrombocytopenia and reduction of the amount of steroid administered.

Rituximab (Anti-CD20 Monoclonal Antibody) in Children with Chronic Refractory Symptomatic Immune Thrombocytopenic Purpura: Efficacy and Safety of Treatment

This retrospective study investigated the effects of rituximab in 19 pediatric patients (15 girls and 4 boys) with chronic refractory symptomatic immune thrombocytopenic purpura (ITP). Patients received from 2 to 5 weekly infusions of rituximab (375 mg/m(2)); 15 patients were younger than 12 years when treated. The median follow-up time was 30 months (range, 9-43 months). The overall response rate was 68% (13/19 patients). Six responders relapsed at a median of 4.5 months (range, 3-8 months). Seven patients still displayed a platelet count >150,000/microL at a median of 33 months (range, 14-43 months) after rituximab treatment. Six of 15 patients treated with 4 or 5 weekly infusions and 1 of 4 patients treated with 2 or 3 infusions are still in remission. No difference was detected between splenectomized and nonsplenectomized patients. The duration of ITP disease at the time of treatment did not influence the response rate. Patients still in remission showed significantly lower levels of CD19+ cells after 4 and 6 months than nonresponding or relapsed patients (P < .05). No major infections were reported during follow-up. Our data show the efficacy and tolerability of rituximab in young children with refractory symptomatic ITP. Nonrelapsed patients showed a more prolonged B-cell depletion.

Eltrombopag: the emerging evidence of its therapeutic value in thrombocytopenia

Idiopathic (immune) thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet counts and bleeding episodes. Current therapy options are associated with unwanted side effects, and although patients initially respond to treatment the platelet count is not sustained in many individuals. There is a need for safe and well-tolerated treatments that provide a sustained platelet response. This review summarizes the emerging evidence for the potential use of eltrombopag in the treatment of ITP in adults. Eltrombopag is a nonpeptide, small molecular weight thrombopoietin receptor agonist that is orally administered. It mimics the activity of thrombopoietin, a cytokine that promotes growth and production of platelets, primarily inducing proliferation and differentiation of megakaryocytes from bone marrow progenitor cells. Eltrombopag is still in the early stages of development but initial phase I and phase II results are promising. Potential advantages of eltrombopag may include a sustained platelet response and a good tolerability profile. Its once-daily oral dosing regimen would also be an advantage over many of the existing therapies. It is expected that patients who have failed first-line therapy with corticosteroids and wish to avoid the need for a splenectomy, and patients with chronic refractory ITP, may benefit from eltrombopag treatment.

Putting the “Tux” on ITP

Bennett and colleagues report that approximately one third of children and adolescents with severe or refractory chronic immune thrombocytopenic purpura (ITP) showed a sustained response to treatment with the monoclonal anti-C20 antibody, rituximab. This prospective study is notable for several

Chronic Refractory ITP in Children: Beyond Splenectomy

Idiopathic (or immune) thrombocytopenic purpura (ITP) is a relatively common hematologic condition, but one that the hematology community has failed to reach a consensus on with regard to treatment. In patients with chronic refractory ITP, there is even less agreement about treatment approaches, as this population represents a small, but challenging, fraction of the total cases of ITP. The aim of this article is to review the treatment options available for children with chronic refractory ITP, including a review of the benefits versus risks, rate of remission, and areas of ongoing and future research.

Recent Advances in the Treatment of Chronic Refractory Immune Thrombocytopenic Purpura

We define chronic refractory immune thrombocytopenic purpura (ITP) as ITP with persistent thrombocytopenia following treatment with glucocorticoids and splenectomy. Chronic refractory ITP is uncommon, occurring in fewer than 10% of all adult patients with ITP diagnoses. The goal of treatment is only to achieve a safe platelet count with minimal treatment-related risk. A safe platelet count may be considered to be as low as 10,000/microL, because the risk for major bleeding in otherwise healthy subjects is great only when the platelet count is less than 10,000/microL. Observation without specific treatment is appropriate for patients with moderate thrombocytopenia and no clinically important bleeding symptoms. For patients with chronic refractory ITP who require treatment, there is no consensus for what therapies to use or the sequence in which to use them. For patients with severe and symptomatic thrombocytopenia, the use of anti-CD20 (rituximab) and immunosuppressive agents, alone or in combination, may be most effective. The mechanism of all current therapies is to decrease the accelerated platelet destruction brought about by immunosuppression. An alternative approach, the stimulation of platelet production with thrombopoietic agents, has been successful in investigational studies and may provide a new management option.

Fc Receptor Blockade in Patients with Refractory Chronic Immune Thrombocytopenic Purpura with Anti-D IgG

Background This is an evaluation of the treatment of 63 patients with chronic immune thrombocytopenic purpura (54 splenectomized and nine nonsplenectomized) with weekly doses of anti-D (IgG)-coated red blood cells (RBCs). Methods All patients were given one 5–15 μg/kg/dose of intravenous (i.v.) anti-D (IgG)-coated RBCs per week (average of 300 μg/dose/week) for a median 3-month period (3–6 months). Treatment modality was evaluated on a weekly basis by platelet counts, measuring of hemoglobin levels, and performance of Coombs tests. Results All patients presented a clinical response. Fifty-two patients (82.5%) increased their platelet count (PC) and 45 (69.8%) increased their PC >50 × 10 9/L. In 34 cases, response was sustained. Six of nine nonsplenectomized patients (67%) increased PC, thus avoiding splenectomy; four patients attained a stable complete response (CR). Similar platelet responses were observed in homozygous and heterozygous Rh (D)-positive patients (Rh/Hr phenotypes). Currently, after >10 years, 43 patients present a now permanent complete response with platelet count >50 × 10 9/L. Ten patients subsequently decreased their platelet count, although they were able to attain CR after receiving six doses of anti-D (IgG)-coated RBCs. Conclusions Based on our study of Fc receptor blockade treatment with anti-D (IgG)-coated RBCs with the most difficult cases of ITP, which resulted in a 69.8% successful response rate, we concluded that weekly prescription of anti-D (IgG)-coated RBCs is an effective approach to treating chronic refractory ITP.

Oral cyclic megadose methylprednisolone therapy for chronic immune thrombocytopenic purpura in childhood.

The objectives of this study were to investigate the effectiveness of oral megadose methylprednisolone (OMMP) therapy in children with chronic immune thrombocytopenic purpura (ITP). Twenty-two patients were given oral methylprednisolone daily for 7 d (30 mg/kg for 3 d and then 20 mg/kg for 4 d). OMMP therapy was repeated once per month if the platelet count was less than 20,000/mm3 at the 30th day of therapy, for up to six courses. The number of platelets of all patients increased gradually during the OMMP therapy, with a peak number at the 7th day, then decreased until the 14th day, and remained relatively stable until 12 months. During the study no patient had a platelet count less than 20,000/mm3 at the 3rd day and 50,000/mm3 at the 7th day. Although the number of platelets was gradually decreased between the 7th and 14th days, it remained above 100,000/mm3 for at least 12 months in the nine patients, and above 20,000/mm3 in the four patients. None of these 13 patients required hospitalization or therapy during the follow-up period. All of the patients tolerated the medication well. None of them reported side-effects that were severe enough to discontinue therapy. We conclude that OMMP therapy is a safe, easy and effective therapy in children with refractory chronic ITP, and it may provide long-term remission in about two thirds of the patients.

Therapy for adults with refractory chronic immune thrombocytopenic purpura.

Adult chronic immune thrombocytopenic purpura (ITP) is a common hematologic disorder; about 14,000 to 16,000 new cases occur each year in the United States. Initial treatment with corticosteroids and splenectomy results in normal or "safe" platelet counts in more than 70% of patients. Treatment of patients refractory to these two treatments is difficult. This paper describes a structured approach to therapy that is based on a literature review and personal experience, including experience with treatment of chronic ITP in special situations (such as emergent bleeding, pregnancy, and central nervous system bleeding). Treatment of most patients with chronic ITP is fairly straightforward, but management of patients refractory to corticosteroids and splenectomy can be difficult. Large, randomized studies are clearly needed to better evaluate the many types of treatment that are recommended for refractory patients.

2-Chlorodeoxyadenosine in the treatment of chronic refractory immune thrombocytopenic purpura [letter

2-Chlorodeoxyadenosine in the treatment of chronic refractory immune thrombocytopenic purpura [letter