TEAM Conditioning (Thiotepa, Etoposide, Cytarabine, Melphalan) Prior to Autologous Hematopoietic Stem Cell Transplantation for Hodgkin and Non-Hodgkin Lymphoma: Final Results from a Prospective Multicenter Study

Introduction

Although a large variety of conditioning regimens are used in autologous hematopoietic stem cell transplantation (autoSCT), including the widely used BEAM (carmustine, etoposide, cytarabine, melphalan), there is no consensus regarding a standard approach. In the context of a carmustine shortage, we replaced it with thiotepa. However, clinical data on the TEAM (thiotepa, etoposide, cytarabine, melphalan) conditioning regimen are sparse and only retrospective. Thus, we designed a multicenter prospective study (NCT02504190) to assess the efficacy and toxicity of a TEAM conditioning regimen.

Patients and methods

The TEAM regimen consisted of a total dose of thiotepa of 8 mg/kg on day -6; etoposide 100 mg/m²/12h and cytarabine 200 mg/m²/12h (day -5 to -2); melphalan 200 mg/m² on day-1. Inclusion criteria were the following: age between 18 and 65 years, biopsy-proven Hodgkin or non-Hodgkin lymphoma, HIV seronegative, and first autoSCT.

Results

Seventy-four male and eighteen female patients with a median age of 53 years (range, 19-65) were included. Karnofsky score was <90% in 17 patients (18%). Lymphoma diagnoses comprised diffuse large B cell (n=48), mantle cell (n=8), follicular (n=12), Hodgkin (n=14), peripheral T-cell (n=9) and miscellaneous (n=4). Advanced stage disease (Ann Arbor stage III-IV) was noted in 83 patients (90%). Disease status at time of autoSCT was complete response (CR) in 69 patients (75%), partial response in 22 (24%), including 12 patients who never reached CR, and progressive disease in 1 (1%). Median number CD34+ cells infused in the graft were 4.6x10e6/kg (range, 1.39-12.7).

Median time to neutrophil recovery was 12 days (range, 9-48) and to platelet recovery >20 G/L was 13 days (range, 7-197). The most significant regimen-related toxicities were mucositis in 100% of patients (median grade=3, range, 1-4) and diarrhea in 98% of patients (median grade=1, range, 0-3). Other non-hematologic grade 3 adverse events occurred in 17 patients (18%). Blood cultures were positive for Staphyloccocus sp. in 27% patents, other Gram- positive bacteria in 5% and Gram negative in 6%. Central line-associated bloodstream infection occurred in 22 patients (24%). Invasive fungal infection occurred in 3 patients. Four patients required transfer to the intensive care unit. The median length of stay in hospital was 27 days (range, 16-62).

At day+100, 89 patients were evaluable for response and all were in CR. Deaths directly attributed to disease progression or relapse occurred in 5 patients. After a median follow-up of 31 months (range, 15-48), the non-relapse mortality (NRM) was 3.3%. Two patients died of infection during aplasia and one patient died 67 days after autoSCT of necrotizing fasciitis. At last follow-up, 17 patients (19%) relapsed, 9 died and 83 were alive. The estimated 3-year overall survival (OS) and progression-free survival (PFS) were 90.2% and 77.2%, respectively. In patients with double expressor diffuse large B-cell lymphoma (n=15), the estimated 3-year OS and PFS were 93% and 73%, respectively. None of the 31 patients with intermediate or high-risk CNS international prognostic index experienced CNS relapse.

Conclusion

The TEAM conditioning regimen is a safe and valid platform in autoSCT for patients with high-risk or relapsed/refractory lymphoma. Although mucositis and diarrhea were frequent, the NRM was similar to that reported for BEAM conditioning. Most notably, no CNS relapse occurred in patients at intermediate or high-risk of CNS relapse.