Safety and Efficacy of Thiotepa-Based Conditioning Therapy for Allogeneic Transplantation in Acute Myeloid Leukemia - a Survey from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Background

Thiotepa (TTP) is an alkylating compound with an antineoplastic activity that has been used since the early nineties. However, few studies focused on the analysis of the benefit of TTP in the pre-allogeneic hematopoietic stem cell transplantation (HSCT) conditioning in a specific disease category. Beside its antineoplastic activity, TTP has immunosuppressive properties and the ability to penetrate the blood-brain barrier in conjunction with a good toxicity profile that makes it an attractive compound to use in the transplant setting. Therefore, the aim of the current analysis was to investigate the potential impact of TTP as part of the conditioning therapy for acute myeloid leukemia (AML) patients in first complete remission (CR1) and beyond.

Methods

This retrospective multicentre study was performed by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Inclusion criteria were adults with AML who received TTP as part of the conditioning regimen for first allogeneic HSCT between 1992 and 2012 (median 2008).

Results

A total of 310 patients with AML (13% secondary) were identified. Median age was 46.5 years; 54% were males and 46% females. 14% of the patients received a previous autologous HSCT. Disease status at HSCT was CR1 in 50%, CR2+ in 23.5%, while 26.5% of the patients had an advanced disease at time of transplant. Cytogenetics was good, intermediate and poor in 8%, 69% and 14%, respectively. Transplantation was performed from an haploidentical donor (35%), matched sibling donor (27%), an unrelated donor (20%) or cord blood (18%). Seventy percent of patients received a myeloablative and 30% a reduced-intensity conditioning regimen. TTP was mostly combined with fludarabine (43%), fludarabine + busulfan (32%) and cyclophosphamide (25%). Median dose of TTP was 10 mg/kg (IQR: 10 – 16).

Neutrophil engraftment was 92±3% at a median day of 16 (range, 8 – 38). Mucositis (all grades) occurred in 46.8% of patients with a median day of onset at day 3 after HSCT. Incidence of sinusoidal obstruction syndrome (SOS) was low: 4.3% of patients developed SOS with a median day of onset at day 8 post-transplant.

Non-relapse mortality after 100 days was 19±2%. Incidence of acute GvHD (Grade> II) was 26% at day 100, while chronic GvHD occurred in 28±3% at 3 years (56% with limited and 44% with extensive disease).

204 patients died. Main cause of death was infection (35%), original disease (31%), GvHD (10%), interstitial pneumonia (6%), SOS (2%) and other transplant related causes (15%). Two patients died due to a secondary malignancy (1%).

With a median follow-up of 37 months, non-relapse mortality at 3 years was 38±4%, 50±6% and 45±6% for patients in CR1, CR2+ and advanced disease, respectively (p=0.10). Relapse incidence at 3 years was 20±3% (CR1), 31±5% (CR2+) and 41±5% (advanced disease; p=0.002). Three-year leukemia-free survival and overall survival were 41±1% and 46±4% (CR1), 20±10% and 28±5% (CR2+) and 14±4% and 14±4% (advanced disease), respectively (p<10-4 for both, leukemia-free and overall survival).

Conclusion

This large survey suggests that TTP-based conditioning therapy in AML is feasible and effective, with main outcomes being comparable to results achieved with other regimens. Of note, side effects incidence (e.g. SOS and mucositis) is relatively low. The latter might explain the increased use of this agent in conditioning regimens prior to allogeneic HSCT.