Addition of thiotepa to a busulphan based conditioning regimen does not improve survival in patients allografted for acute myeloid leukaemia and myelodysplasia: Results of the UK impact cosi trial Free

Purpose:Disease relapse remains the major cause of treatment failure in patients allografted for acute myeloid leukaemia (AML) and myelodysplasia (MDS). Accumulating data confirms an important contribution of the conditioning regimen to both disease control and transplant toxicity. Thiotepa (Thio) is an alkylating agent whose addition to a busulphan (Bu)/fludarabine (Flu) conditioning regimen has been shown in retrospective studies to improve survival in patients transplanted for AML using both matched unrelated and haploidentical donors, consequent upon a reduction in post-transplant relapse. As a result, Flu/Bu/Thio conditioning regimens are increasingly used in patients allografted for high risk AML despite the absence of prospective randomised trials supporting this practice. COSI is the first prospective randomised trial to examine the benefit of adding Thio to a Flu/Bu based myeloablative (MAC) or reduced intensity (RIC) conditioning regimen in patients allografted for AML in CR1 or CR2 or IPSS high risk MDS.

Patients and methods:Three hundred and seventeen patients with high risk AML (n= 242: CR1 n=205, CR2 n=37), or MDS (n= 75) were randomly assigned to undergo transplantation from a matched related sibling (n=52) or matched unrelated donor (n=265) using either a Flu/Bu or Flu/Bu/Thio conditioning regimen. Ninety nine patients were transplanted using a MAC regimen (Flu 40 mg/m² x 4 days, Bu 3.2 mg/kg x 4 days or Flu 50 mg/m²x 3 days, Bu 3.2 mg/kg x 3 days, Thio 5 mg/kg x 2 days) and 218 patients using a RIC regimen (Flu 30 mg/m² x 5 days, Bu 3.2 mg/kg x 2 days, or Flu 50 mg/m² x 3 days, Bu 3.2 mg/kg x 2 days, Thio 5 mg/kg x 1 day). All patients received ciclosporin/ATG-based GVHD prophylaxis. The primary endpoint was overall survival (OS). Results will be presented separately for the MAC (Randomisation 2) and RIC (Randomisation 3) arms of COSI, analysed on intent-to-treat basis analyses, adjusted for stratification factors where possible. The median age of the patients randomised to the MAC arm was 44 years (range 20-54 years) for the RIC arm was 64 (range 31-75 years). Pre-transplant measurable residual disease (MRD) was measured 28 days prior to transplant by flow cytometry (MFC-MRD) and correlated with outcome in both the MAC and RIC arms, using an MRD threshold of 0.1%.

Results:In the 99 patients randomised to the MAC arm, addition of Thio to a Flu/Bu₄ conditioning regimen did not increase 2 year OS: 75% using Flu/Bu₄ versus 72% using Flu/Bu₃/Thio (p=0.73). In patients who were MRD negative pre-transplant 2 year OS in patients transplanted using Flu/Bu₄ was 81% versus 70% in patients transplanted using Flu/Bu₃/Thio (p=0.91). In patients who were MRD positive pre-transplant 2 year OS using Flu/Bu₄was 67% versus 63% for patients transplanted using Flu/Bu₃/Thio (p=0.55). The 2 year cumulative incidence of relapse (CIR) was lower in patients transplanted using a Flu/Bu₄/Thio conditioning regimen: 11% using Flu/Bu₄/Thio versus 31% using Flu/Bu₄ (p=<0.001). However, in contrast the 2-year transplant-related mortality (TRM) in patients transplanted using a Flu/Bu₄/Thio regimen was increased: 22% using Flu/Bu₄/Thio versus 4% using Flu/Bu₄ (p=<0.001). In the 218 patients randomised to the RIC arm the addition of Thio did not increase 2 year OS: 71% using Flu/Bu₂versus 69% using Flu/Bu₂/Thio (p=0.87). In patients who were MRD negative pre-transplant 2 year OS was 84% using Flu/Bu₂versus 75% for patients transplanted using Flu/Bu₂/Thio (p=0.45). In patients who were MRD positive pre-transplant 2 year OS was 56% using Flu/Bu₂/Thio versus 41% in patients transplanted using Flu/Bu₂ (p=0.15). The 2 year TRM in patients transplanted using a Flu/Bu₂/Thio regimen was increased: 17% using Flu/Bu₂/Thio versus 8% using Flu/Bu₂ (p=0.01). The 2 year CIR in patients transplanted using a Flu/Bu₂/Thio regimen was 20% versus 30% in patients transplanted using a Flu/Bu₂ regimen (p=0.12).

Conclusion:This prospective randomised trial demonstrates that the addition of Thio to either a Flu/Bu based MAC or RIC regimen does not improve survival in patients allografted for AML or MDS and was associated with an increased TRM in both settings. Further prospective studies examining the ability of Thio to reduce the risk of disease relapse in high risk patients whilst at the same time limiting transplant toxicity are merited.