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Charles S. Abrams, MD, University of PennsylvaniaDecember 9-12, 2006Orlando, FloridaCharles S. Abrams, MD, University of Pennsylvania

It has been over 50 years since Harrington and colleagues became thrombocytopenic by infusing themselves with plasma derived from patients with immune thrombocytopenic purpura (ITP).[[1]]( "_ednref1") This classic experiment demonstrated that a plasma component, subsequently shown to be immunoglobulin was the essential component of immune mediated platelet destruction that defines ITP.  Since platelet production is assumed to be increased, traditional therapy has focused on moderating this immune response that leads to accelerated platelet destruction.

Although the vast majority of patients do have a compensatory increase in megakaryopoiesis, curiously, plasma derived from some ITP patients can actually inhibit platelet production. This has prompted a re-evaluation of whether impaired megakaryopoiesis is another mechanism for the thrombocytopenia in this disease. Thrombopoietin (TPO) levels are not markedly elevated in ITP, implying that there are normal or increased numbers of megakaryocytes in the bone marrow of these patients.  With this perspective, thrombopoietin levels are actually not inappropriately low for the degree of thrombocytopenia. However, it also suggests that supplemental thrombopoietin could help increase platelet production by overdriving the system, and thereby correcting the thrombocytopenia.

History of Thrombopoietin Use in Man

Cloned almost simultaneously by several research groups in 1994, human thrombopoietin is composed of 353 amino acids.  Thrombopoietin is a potent megakaryocyte colony-stimulating factor, and along with other cytokines increases the size and number of megakaryocytes.  When administered to humans and other primates, thrombopoietin increases the number of marrow megakaryocytes and circulating platelets up to 10-fold.  A truncated form of thrombopoietin called megakaryocyte growth and developmental factor (MGDF) coupled to polyethylene glycol (PEG) has also been administered to a variety of thrombocytopenic patients.  Both recombinant thrombopoietin and PEG-MGDF clearly shortened the period required for platelet counts to return to normal following systemic chemotherapy.  Although initial reports implied that recombinant thrombopoietin had minor toxicity, one subject given this drug developed non-neutralizing antibodies.  In addition, several patients receiving PEG-MDGF developed neutralizing antibodies against their endogenous thrombopoietin resulting in profound and persistent thrombocytopenia.[[2]]( "_ednref2") Largely because of this toxicity, both recombinant thrombopoietin and PEG-MGDF were withdrawn from clinical trials.

TPO-Mimetics:  The Next Generation 

By screening peptide libraries, several groups were able to identify peptides that bind the TPO receptor with high affinity. Because they bear no structural resemblance to TPO, but still bind and activate the TPO receptor, these compounds are called TPO mimetics.  Several peptides have been identified, and they have been further modified to both prolong their half-life in plasma as well as to increase their efficiency in activating the TPO receptor.  The theoretical advantage of these compounds over standard recombinant thrombopoietin is that they bear little structural similarity with native thrombopoietin, and should not trigger auto-immune anti-thrombopoietin antibodies like PEG-MDGF. 

AMG 531 is the most developed pharmaceutical in the peptide TPO mimetic category.  It is composed of several copies of the TPO receptor-binding peptide spliced into a recombinant antibody.  This peptide mimetic competes with thrombopoietin for binding to the TPO receptor, and activates the receptor in an identical fashion to endogenous thrombopoietin.  When administered subcutaneously to humans, AMG 531 produces a dose-dependent increase in platelets counts. 

A similar approach has been used to identify other small molecules capable of binding and activating the TPO receptor, yet bear little structural similarity to thrombopoietin.  Screening small molecule libraries for compounds that have TPO-like activity identified these so called TPO nonpeptide mimetics.   The most developmentally advanced of this category is Eltrombopag.  It is an orally available drug that activates the TPO receptor by binding to the receptor’s transmembrane region.  Therefore, unlike AMG 531, Eltrombopag does not compete with endogenous thrombopoietin for binding to the TPO receptor.  Like subcutaneously administered AMG 531, oral Eltrombopag also produces a dose-dependent increase in the platelet count of healthy volunteers.  Although not as far along in clinical trials, several other oral TPO nonpeptide mimetics including AKR-501 and SB-559448 are also currently being developed and appear to show good thrombopoietic activity in humans. 

TPO-Mimetics and ITP

Since thrombopoietin levels are not extremely elevated in the plasma of patients with ITP, it seemed reasonable to attempt to ramp up platelet production with the administration of exogenous thrombopoietin.  In 2002, S. Nomura et al. demonstrated that seven daily doses of PEG-MGDF significantly increased the platelet count in two out of four refractory ITP patients.[[3]]( "_ednref3") Although this appeared promising, as mentioned previously, PEG-MGDF development was halted because of its propensity to induce autoimmune antibodies against endogenous thrombopoietin.  Once TPO-mimetics became available, several groups analyzed whether these compounds would also increase platelet counts in patients with ITP without inducing an immunotoxicity. 

The first Phase II trial to test this hypothesis was recently published.[[4]]( "_ednref4") Sixteen ITP patients who had previously been treated with at least one prior form of therapy were enrolled in a double-blind, placebo controlled trial of AMG 531.  Patients were treated with six weekly subcutaneous injections of 1 or 3 micrograms/kg of AMG 531.  This peptide TPO-mimetic increased the platelet count to greater than 50,000/µl in twelve patients (75%), including two patients in the 3 microgram/kg dose group who had platelet counts that exceeded 500,000/µl.  There appeared to be no relationship between baseline thrombopoietin levels and platelet responses implying that one is able to overdrive platelet production even in patients with appropriate (i.e. normal) thrombopoietin levels. Reassuringly, no thrombotic complications were found, and the overall toxicity was low. 

ASH 2006

At the American Society of Hematology Meeting In December, three significant abstracts were presented that furthered our knowledge of the use of TPO mimetics in ITP. 

Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 48-week update.[[5]]( "_ednref5")

AMG 531 is a peptide-base TPO-mimetic with no sequence homology to thrombopoietin. This study sought to determine the long-term safety profile of this drug in patients previously enrolled in other clinical trials of AMG 531.  The authors reported the outcome of 36 ITP patients who continued to receive weekly subcutaneous injections of the study drug. Twenty-nine patients received AMG 531 for longer than 48 weeks. Eighty-six percent of patients had a platelet response defined as at least double the baseline platelet count, and at least 50,000/µl.  Most of all of the responding patients had platelet counts greater than 150,000/µl. The most frequent adverse events were headache, upper respiratory tract infection, and fatigue. Of concern, one patient developed treatment-related bone marrow reticulin fibrosis, although this reversed upon discontinuation of the drug. Overall, the results showed that long-term treatment with this TPO mimetic might be a viable therapeutic option for patients with refractory ITP.

Analysis of bleeding in patients with immune thrombocytopenic purpura (ITP): A randomized, double-blind, placebo-controlled trial of eltrombopag, an oral platelet growth factor.[[6]]( "_ednref6")

Eltrombopag is an oral non-peptide thrombopoietin receptor agonist with a low immunogenic potential.  A Phase I trial of 73 subjects was previously presented demonstrating that this drug increases the platelet counts in healthy volunteers in a dose-dependent fashion.  Presented at the recent ASH meeting were the results of a Phase II placebo-controlled double-blind trial.  In this study, the platelet counts of 117 patients with chronic ITP were analyzed after 6 weeks of therapy with 30, 50, or 75 mg of daily eltrombopag. Notably, all patients in this trial had at least one prior form of therapy, and the patients were allowed to continue prednisone therapy while they received the test drug. Approximately 75% of the ITP patients exposed to the two higher daily doses of eltrombopag for 6 weeks had a median platelet count greater than 50,000/µl, and 40% of the patients had a platelet count greater than 200,000/µl. In contrast, patients receiving placebo had a mean platelet count of 16,000/µl.  Headache was the most common adverse event, and the remaining adverse events were mild.  The data presented thus far, suggests that eltrombopag is a well-tolerated oral TPO-mimetic with excellent response rates in the treatment of chronic ITP. 

Single and multiple oral doses of AKR-501 (YM477) increase the platelet count in healthy volunteers.[[7]]( "_ednref7")

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This abstract described the first time in man experience with AKR-501, an oral TPO-mimetic. This included a Phase I single-dose study of healthy volunteers exposed to escalating doses of AKR-501.  A response was defined as a greater than 50% increase in their platelet count, and this was identified in five of the six subjects exposed to a single 100 mg preparation of AKR-501.  Also reported was a Phase I multi-dose trial of AKR-501. When exposed to two weeks of daily oral dosing, all subjects exposed to either 10 or 20 mg of this drug increased their platelet counts to greater than 150,000/µl. The most frequent side effect reported was an unpleasant sensation of taste, but overall the drug was well tolerated.  This abstract demonstrated that at least in healthy volunteers, AKR-501 is an effective agent at increasing platelet counts.

Although there was certainly a lot of interest in the use of TPO-mimetics in ITP, three ASH abstracts that utilized new or experimental forms of immunosuppression were noteworthy.

Efficacy and safety of rituximab in the treatment of refractory/relapsed idiopathic-thrombocytopenic purpura (ITP): Results of a meta-analysis of 299 patients.[[8]]( "_ednref8")

The monoclonal antibody against CD20-positive B cells, Rituxan® (rituximab) has received recent enthusiasm as an immunosuppressive agent.  It is clear that Rituxan can induce remissions in ITP, although it has been difficult to estimate its true efficacy since the literature is biased by small case series touting high response rates. By restricting analysis to publications that report response rates based on more than 5 patients, the authors identified 15 papers that focused on Rituxan efficacy in ITP.  Pooling this data together, the responses in 299 ITP patients were analyzed.  The overall response rate to Rituxan was 55%, including 38% who had a complete response (defined as a platelet count greater than 100,000/µl). This places the response rate of Rituxan in the same category, but probably not better than most other immunosuppressive agents. However, Rituxan still does have the advantage of a relatively good safety profile. 

Rituximab is an alternative to splenectomy in adults with chronic immune thrombocytopenic purpura: Results of a multicenter prospective phase 2 study.[[9]]( "_ednref9")

Splenectomy has long been considered the gold standard of therapy for patients who require treatment for chronic ITP.  It produces long-term response rates of 65-70%, and many of the remaining patients derive some benefit from the procedure. Although splenectomy has an impressive response rate, it is associated with approximately 1% operative mortality, as well as a lifelong increased risk of opportunistic infections. Rituxan probably also carries a long-term risk of infections, but other than allergic reactions and serum sickness, it is not associated with significant short term morbidity or mortality. The multicenter single arm trial described in this abstract sought to determine whether four 375mg/m2 weekly doses of Rituxan would cause a sustained increase in platelet counts.  Sixty patients with average platelet counts of 16,000/µl received Rituxan, and most of these patients tolerated the treatment well. Twenty-four patients (40%) achieved a platelet count of at least twice their baseline, and greater than 50,000/µl.  Eleven months after completion of therapy, 18 of the 24 responders had a platelet count greater than 150,000/µl, and the remaining 6 patients had a platelet count greater than 50,000/µl. These results, along with the above mentioned meta-analysis, show that approximately forty percent of ITP patients respond to Rituxan.  Reassuringly, this current abstract also demonstrates that when patients do benefit from Rituxan treatment, the responses are frequently durable. 

Treatment of refractory ITP: efficacy of Fcγ-RIII blockade.[[10]]( "_ednref10")

In patients with ITP, thrombocytopenia results from an interaction between platelet surface bound immunoglobulin and Fcγ-RIII receptors on macrophages. In theory, blocking macrophage Fcγ-RIII receptors might prevent macrophages from clearing platelets from the circulation.  To minimize the serum sickness associated with early trials of a mouse antibody against the human Fcγ-RIII receptor; this abstract describes the use of GMA-161, a humanized version of this antbody. Four patients with chronic refractory ITP received the lowest dose of GMA-161.  Although two patients did have a significant response to this antibody, the responses were short lived and associated with transient leukopenia.  The idea of therapeutically targeting the Fcγ-RIII receptor is appealing and certainly novel, but it may be associated with too significant side effects to have general applicability for the treatment of ITP.


[[1]]( "_edn1")J Lab and Clin Medicine 1951;38(1):1-10.

[[2]]( "_edn2") Li j, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 2001;98:3241-3248.

[[3]]( "_edn3") Nomura S, Dan K, Hotta T, et al. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood 2002:100:728-730.

[[4]]( "_edn4") Bussel JB, Kuter DJ, George JN, et al.AMG 531, a Thrombopoiesis-Stimulating Protein, for Chronic ITP. N Eng J Med;355:1672-1681.

[[5]]( "_edn5") Kuter D, Bussel, J, George J, et al. Long-term dosing of AMG 531 in thrombocytopenic patients with immune thrombocytopenic purpura: 48-week update. Blood 2006;108:168, abstract 476.

[[6]]( "_edn6") Bussel JB, Cheng G, Saleh M, et al. Analysis of bleeding in patients with immune thrombocytopenic purpura (ITP): A randomized, double-blind, placebo-controlled trial of Eltrombopag, an oral platelet growth factor. Blood 2006;108:168, abstract 475.

[[7]]( "_edn7") Desjardins RE, Tempel DL, Lucek R, et al. Single and multiple oral doses of AKR-501 (YM477) increase the platelet count in healthy volunteers. Blood 2006;108:168, abstract 477.

[[8]]( "_edn8") Ramanarayanan J, Brodzik F, Czuczman MS, et al. Efficacy and safety of Rituximab in the treatment of refractory/relapsed idiopathic-thrombocytopenic purpura (ITP): Results of a meta-analysis of 299 patients. Blood 2006;108:321a, abstract 1076.

[[9]]( "_edn9") Godeau B, Fain O, Porcher R, et al. Rituximab is an alternative to splenectomy in adults with chronic immune thrombocytopenic purpura: Results of a multicenter prospective phase 2 study. Blood2006;108:145a, abstract 478.

[[10]]( "_edn10") Bussel JB, Patel V, Dunbar C, et al. Treatment of refractory ITP: Efficacy of Fcγ-RIII blockade. Blood2006;108:320a, abstract 1073.