Thiotepa, Busulfan and Fludarabine Conditioning Regimen in Adult Patients Undergoing Allogeneic Stem Cell Transplantation for Lymphoid Malignancies. a Study on Behalf of Geth-TC

Background: The optimal conditioning regimen in allogeneic hematopoietic stem cell transplant (alloHCT) for lymphoid malignancies remains unclear. Reduced intensity regimens (RIC) allow older and more comorbid patients to receive alloHCT since lower non-relapse mortality (NRM) is observed, but disease control may still be a concern. The use of reduced toxicity conditioning regimens allows better disease control with a cost of higher toxicity. To date, no data are available regarding the use of thiotepa, busulfan and fludarabine (TBF) in adult patients allografted for lymphoma. Our aim is to describe survival outcomes and treatment-related toxicities of patients with lymphoid malignancies conditioned with TBF.

Methods: Between December 2011 and July 2022, 116 patients diagnosed with lymphoid malignancies received a first alloHCT conditioned with a TBF-based regimen in 9 Spanish institutions. All consecutive patients were included in the study and data were collected retrospectively. Low-dose TBF was defined as the use of 5 mg/kg of thiotepa (T5) while a high-dose TBF was considered as the administration of 10 mg/Kg of thiotepa (T10). Main outcome variables were overall survival (OS), progression-free survival (PFS), NRM, relapse incidence (RI), cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD), and hematological recovery. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator method, and NRM, RI, GVHD and hematological recovery as cumulative incidences.

Results: Baseline characteristics are summarized in Table 1. The median age was 52 (range 23-70) years and 62.1% of the patients were males. Aggressive B-cell lymphoma was the most common diagnosis (43.1%). Seventy-seven (66.4%) patients received T10, and 39 (33.6) T5. Median follow-up among survivors was 46.9 (range 16.9-136.5) months. At 3 years, OS, PFS, NRM and RI were 54.7% (95% confidence interval [CI], 45.5-63.9%) ( Figure 1), 44.9% (95% CI, 35.7-54.1%), 34.9% (95% CI, 27.1-44.9%) and 20.2% (95% CI, 14-29.2%), respectively. Of the 53 patients who died during follow up, causes of death were: 12 relapses and 41 transplant toxicities (16=infections, 8=GVHD, 5=endothelial complications, 1=traumatism, 11=missing). Fifty-one percent of toxicity-related deaths were observed during the first 3 months from transplant. All but 2 patients engrafted. The cumulative incidence of neutrophil engraftment at day +30 was 91.4% (95% CI, 86.3-96.8%). The cumulative incidence of grade II-IV aGVHD at day +100 was 25.4% (95% IC, 18.5-34.9%), with 8 patients presenting grade III-IV aGVHD. The 3-years cumulative incidence of all grade cGVHD was 29.8% (95% CI, 22.5-39.6%), with 15 patients presenting with moderate-severe cGVHD. Seventeen patients developed venooclusive disease (14.7%) with a median time from alloHCT infusion of 14 (range 7-93) days.

On univariate analysis, no prognostic factors were found in terms of NRM, OS and PFS. However, higher doses of thiotepa were associated to a lower relapse incidence (13.2% vs 35%, p=0.0075) without differences in terms of NRM. The use of myeloablative conditioning (vs RIC) showed a trend towards a lower relapse incidence although it was not statistically significant (9.4% vs 24.5%, p=0.059) with no impact in NRM rates. On multivariate analysis these results could not be confirmed.

Conclusions: In our series, TBF conditioning regimen allows efficient disease control at the expense of increased incidence of severe early toxicities. Despite higher NRM, TBF conditioning regimen showed similar OS rated compared to other regimens used for lymphoid malignancies. This regimen could be considered for fit patients with high-risk lymphoid diseases.