Eltrombopag in Patients With Delayed Post Transplant Thrombocytopenia. (ITP0511)
This is a Phase II multicentre study. Patients will be administered eltrombopag 50 mg/daily. If patients don't achieve response after 2 months of therapy they will stop eltrombopag; if patients will achieve response after 2 months of therapy, they will continue eltrombopag for a maximum period of 24 months; 40 patients are needed. In stage I, 22 patients will be enrolled; if ≤ 4 responses at the first evaluation after 2 months (18%) will be seen, the trial will be stopped; if 5 or more responses will be seen, the accrual will continue. In stage II, 18 more patients will be enrolled. If ≤ 12 (30%) responses will be observed out of 40 patients, it will be concluded that the study drug is not active enough. If ≥ 13 responses will be observed, it will be concluded that eltrombopag is worth of further studies.
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Eltrombopag in Patients With Delayed Post Transplant Thrombocytopenia.|
- Number of patients who achieve both a platelet count ≥ 50 x 109/L and have doubled their baseline platelet count. [ Time Frame: Two months after treatment with eltrombopag. ] [ Designated as safety issue: No ]Response rate (OR), i.e. the number of patients who achieve both a platelet count ≥ 50 x 109/L and have doubled their baseline platelet count, two months after treatment with eltrombopag. The primary endpoint will be considered for all the treated population according to the intention-to-treat and in the evaluable population, i.e. all patients treated with eltrombopag for at least 3 weeks or who interrupted eltrombopag because of toxic events. A transient increase of platelet count after the administration of iv immunoglobulin given for anti- microbial purpose will not be considered criteria of response.
- Number of adverse events. [ Time Frame: After 4 years from study entry. ] [ Designated as safety issue: Yes ]Safety profile Incidence of AEs according to NCI Common Terminology Criteria for Adverse Events v 4.0 [NCI CTCAE] toxicity scale.
- Number of surviving patients. [ Time Frame: At 4 years from study entry. ] [ Designated as safety issue: No ]Overall Survival OS will be evaluated with Kaplan Meyer and compared with historical patients who developed post SCT delayed thrombocytopenia.
- Number of bleeding events. [ Time Frame: After 4 years from study entry. ] [ Designated as safety issue: Yes ]Bleeding events Bleeding events will be evaluated according to the WHO bleeding scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; grade 4, debilitating blood loss).
- Characteristics of TPO serum level. [ Time Frame: After 4 years from study entry. ] [ Designated as safety issue: No ]TPO serum level TPO will be measured using a Human TPO duo-set assay (R&D System). This assay employs the quantitative sandwich enzyme immunoassay technique to evaluate the concentration of TPO in plasma or serum.
- Patients T-reg activity. [ Time Frame: After 4 years from study entry. ] [ Designated as safety issue: No ]T-reg activity T-reg activity will be evaluated by flow cytometric analysis of CD4+ CD25+ FOXP3+ lymphocytes in a mixed lymphocyte population.
|Study Start Date:||September 2013|
|Estimated Study Completion Date:||November 2017|
|Estimated Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
The incidence of delayed thrombocytopenia in patients who undergo allogeneic hemopoietic stem cell transplant (SCT) is nearly 20-40% (1-2). Chronic graft versus host disease (cGVHD) seems to be the most frequent pathologic condition associated with post SCT delayed thrombocytopenia. Previous studies indicated the occurrence of delayed thrombocytopenia as a poor prognostic factor for the outcome of patients undergoing SCT, particularly for those patients with cGVHD. In our experience, 27 out of 71 patients (38%) developed post SCT delayed thrombocytopenia, with a median platelet count of 29 x 109/L (range 7-86 x 109/L); cGVHD was associated with delayed thrombocytopenia in 54% of cases. The platelet count was >50 <100 x 109/L in 8 patients (30%) patients and 50 x 109/L in 19 (70%) among whom 9 had 20 x 109/L. The median post SCT survival was 12 months in patients who developed delayed thrombocytopenia vs. > 36 months in patients without delayed thrombocytopenia. The rate of patients alive 12, 24 and 33 months after SCT was 41%, 41% and 7% among patients with delayed thrombocytopenia vs. 93%, 87% and 87% (p< 0.0001). In patients with cGVHD the incidence of mortality was significantly higher in those who developed post SCT thrombocytopenia, i.e. 8 out of 13 (61.5%) vs. 2 out of 19 (10.5%) (p=0.005). Our data confirms the results of previous studies. Therefore, the occurrence of delayed thrombocytopenia in patients undergoing SCT is a very poor prognostic factor and the improvement of this condition may favourably affect patients' outcome. The pathophysiology of cGVHD relayed post SCT delayed thrombocytopenia is complex and only partial understood. Biological and clinical evidences support an autoimmune-like thrombocytopenia with increased platelet destruction; this mechanism is also suggested by the response to some therapeutic strategies generally adopted to treat classical immune thrombocytopenia as steroids, high dose intravenous immunoglobulin, splenectomy, rituximab. However a mechanism consistent with impaired platelet production has also been suggested. Adopting an index for plasma glycocalicin, plasma thrombopoietin (TPO), and circulating B cells producing anti-GPIIb-IIIa antibodies, Yamazaki et al. studied 23 SCT recipients who had prolonged and isolated thrombocytopenia with no apparent causes such as engraftment failure, recurrence of the underlying malignancy, microangiopathy or drugs and compared data with those observed in a similar cohort of SCT recipients with no thrombocytopenia, in patients with primary immune thrombocytopenia (ITP) and aplastic anemia. Despite the frequent occurrence of an antiplatelet antibody response, patients with post SCT thrombocytopenia showed a glycocalicin index and TPO status similar to that seen in aplastic anemia. TPO levels were normal in nearly 30% of patients. Recently, Bao et al. showed an improved regulatory T-cell (T-regs) activity in patients with chronic primary immune thrombocytopenia (ITP) treated with thrombolytic agents, suggesting a possible role of platelet count in improving T-reg function and restore immune tolerance.
On this grounds and similarly to ITP, the stimulation of thrombopoiesis with the thrombolytic agents could be beneficial in some patients with persistent post SCT thrombocytopenia both on platelet count and on cGVHD manifestations. Eltrombopag (Revolade) is a thrombopoietin receptor agonist indicated for the treatment of adult patients with ITP relapsed/refractory to splenectomy; eltrombopag may be considered as second line treatment for adult non-splenectomised patients where surgery is contraindicated. Eltrombopag is also under development for the treatment of thrombocytopenia due to hepatitis C virus HCV, for chemotherapy-induced thrombocytopenia and in MDS/AML.
|Contact: Paola Fazi, Dr.||firstname.lastname@example.org|
|Contact: Enrico Creaemail@example.com|
|UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro||Not yet recruiting|
|Contact: Giorgina Specchia, Pr.|
|Principal Investigator: Giorgina Specchia, Pr.|
|Sub-Investigator: Domenico Pastore, Dr.|
|Divisione di Ematologia - Ospedali Riuniti||Not yet recruiting|
|Contact: Alessandro Rambaldi|
|Principal Investigator: Alessandro Rambaldi|
|USD Trapianti di midollo per adulti - Cattedra di Ematologia - Università degli Studi di Brescia||Not yet recruiting|
|Contact: Domenico Russo|
|Principal Investigator: Domenico Russo|
|Ospedale Santa Croce Divisione di Ematologia Cuneo||Not yet recruiting|
|Contact: Giuseppe Milone, Dr.|
|Principal Investigator: Giuseppe Milone, Dr.|
|Sub-Investigator: Salvatore Leotta, Dr.|
|Ospedale Santa Croce Divisione di Ematologia Cuneo||Not yet recruiting|
|Contact: Nicola Mordini, Dr.|
|Principal Investigator: Nicola Mordini, Dr.|
|Sub-Investigator: Davide Rapezzi, Dr.|
|Policlinico di Careggi||Not yet recruiting|
|Contact: Alberto Bosi, Dr.|
|Principal Investigator: Alberto Bosi, Dr.|
|Sub-Investigator: Stefano Guidi, Dr.|
|Divisione Ematologia 2 - Azienda Ospedaliera Universitaria - S.Martino||Not yet recruiting|
|Contact: Andrea Bacigalupo, Dr.|
|Principal Investigator: Andrea Bacigalupo, Dr.|
|Unità Trapianto di Midollo Ist. Nazionale Tumori||Not yet recruiting|
|Contact: Paolo Corradini|
|Principal Investigator: Paolo Corradini|
|Sub-Investigator: Francesco Spina|
|La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello||Not yet recruiting|
|Contact: Maurizio Musso, Pr.|
|Principal Investigator: Maurizio Musso, Pr.|
|Sub-Investigator: Alessandra Crescimano, Dr.|
|U.O. Ematologia Clinica - Azienda USL di Pescara||Not yet recruiting|
|Contact: Pasqua Bavaro, Dr.|
|Principal Investigator: Pasqua Bavaro, Dr.|
|Sub-Investigator: Elsa Pennese, Dr.|
|Università Cattolica del Sacro Cuore - Policlinico A. Gemelli||Not yet recruiting|
|Contact: Simona Sica|
|Principal Investigator: Simona Sica|
|Università degli Studi - Policlinico di Tor Vergata||Not yet recruiting|
|Contact: Giorgio Arcese|
|Principal Investigator: Giorgio Arcese|
|Sub-Investigator: Alessandra Picardi|
|Clinica Ematologica - Policlinico Universitario||Not yet recruiting|
|Contact: Francesco Zaja, Dr.|
|Principal Investigator: Francesco Zaja, Dr.|
|Sub-Investigator: Marianna Chizzotto, Dr.|
|ULSS N.6 Osp. S. Bortolo||Not yet recruiting|
|Contact: Carlo Borghero, Dr.|
|Principal Investigator: Carlo Borghero, Dr.|
|Principal Investigator:||Francesco Zaja||Clinica Ematologica, DISM, Azienda Ospedaliera Universitaria S. M. Misericordia|