Tacrolimus Plus High-Dose Dexamethasone Versus High-Dose Dexamethasone Alone As First-Line Treatment for Adult Immune Thrombocytopenia: The Phase 2, Open Label, Randomized Trial (TARGET 020)

Abstract

Introduction Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission. Methods This open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts <30×10 9/L, or < 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained >50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080). Results Total 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups. Conclusions Low-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: It includes information or discussion of off-label drug use of tacrilimus.

Expert Report on Immune Thrombocytopenia: Current Diagnostics and Treatment – Recommendations from an Expert Group from Austria, Germany, and Switzerland

“…Example calculations for cumulative steroid dose -Prednisolone: 1 mg/kg (70 kg) for 1 week, then taper in weekly 10-mg steps (50 mg → 40 mg → 30 mg → 20 mg → 10 mg) and eventually stop after 6 weeks → cumulative dose mus [42] in first-line achieve 60-70% therapy-free remissions (follow-up time 1 year and longer) and thus significantly greater than corticosteroids alone. However, mycophenolate and tacrolimus are not approved for ITP, and theirpotential side effects might negatively impact patients' quality of life.…”

“…For ITP, it is given as monotherapy or in combination with prednisone. The starting dose is 1 mg BID (in transplant medicine much higher doses of 0.1-0.2 mg/kg/day are given), targeting for a trough level of 4-10 ng/mL [42] The following side effects have been described in the transplant setting: renal insufficiency, cardiomyopathies, intestinal perforation, secondary tumors including lymphomas, and encephalopathy syndromes. Is It Possible to Achieve a Lasting Remission with a Fourth or Further Line of Therapy?…”

“…At the same time, however, a rethinking and paradigm shift has taken place. Two studies have been published recently that did not choose the platelet count response or prevention of bleeding as the main study end-points but rather the number of treatment-free remissions [41,42]. A discussion is needed about whether future ITP studies need new primary endpoints [146]:…”

Expertenreport Immunthrombozytopenie – Aktuelle Diagnostik und Therapie

“…Man hat deshalb versucht, durch die Kombination von Glukokortikoiden mit anderen Wirkstoffen diese Ergebnisse zu verbessern. Die Kombination Glukokortikoid mit Mycophenolat Mofetil [41] oder mit Tacrolimus [42] erreicht in der 1st Line bei ca. 60-70% der Patient*innen therapiefreie Remissionen (Nachbeobachtungszeit 1 Jahr und länger) und damit deutlich mehr als mit einer Glukokortikoid-Monotherapie.…”

“…Gleichzeitig hat in den letzten Jahren aber auch ein Umdenken und Paradigmenwechsel stattgefunden. Aktuell wurden zwei Studien hochrangig publiziert, die nicht das Ansprechen der Thrombozytenzahl oder die Verhinderung von Blutungen, sondern das Erreichen einer therapiefreien Remission als Haupt-Studienendpunkt gewählt haben[41,42]. Man muss jetzt diskutieren, ob die folgenden Kriterien zukünftig vorrangige Beachtung finden sollen[146]: − Erreichen einer therapiefreien Remission, − Verzögerung der Zweitlinientherapie, − Vermeidung einer Splenektomie, − langfristige Verbesserung von gesundheitsbezogener Lebensqualität, − Senkung der Gesamtbehandlungskosten inklusive der indirekten Kosten (Vermeidung stationärer Aufenthalte, von Arbeitsausfall, Zuzahlungen, weniger Zeitaufwand für Kontrollen und Arztbesuche).…”