TBI-containing transplant preparative regimens

Two registry studies and a small randomized trial showed that transplant conditioning regimens that included TBI resulted in higher cure rates than chemotherapy-only preparative regimens.[56,90,91]

An international study (United States, Europe, and Australia) that combined data sets from prospective trials and single-center data showed that the use of non-TBI regimens was an independent risk factor for poor outcome.[74,81,92]

An international phase III trial (the FORUM study) conducted between 2013 and 2018 enrolled 417 pediatric patients aged 4 to 21 years with ALL. Patients were randomly assigned to receive either TBI (12 Gy) with etoposide or chemotherapy only (fludarabine, thiotepa, and busulfan or treosulfan) as a preparative regimen. All patients were in morphological CR at the time of transplant and received a 9/10 or 10/10 matched sibling donor (MSD) or unrelated matched donor (URD) transplant. The intent was to enroll 1,000 patients, but the study was closed to enrollment early when a futility early stopping rule was met, indicating that the chemotherapy-only preparative regimen was associated with an inferior outcome.[93]

An international phase III trial (the FORUM study) conducted between 2013 and 2018 enrolled 417 pediatric patients aged 4 to 21 years with ALL. Patients were randomly assigned to receive either TBI (12 Gy) with etoposide or chemotherapy only (fludarabine, thiotepa, and busulfan or treosulfan) as a preparative regimen. All patients were in morphological CR at the time of transplant and received a 9/10 or 10/10 matched sibling donor (MSD) or unrelated matched donor (URD) transplant. The intent was to enroll 1,000 patients, but the study was closed to enrollment early when a futility early stopping rule was met, indicating that the chemotherapy-only preparative regimen was associated with an inferior outcome.[93]

The 2-year OS rate was 91% for patients who received a TBI-containing regimen, compared with 75% for those who received a chemotherapy-only preparative regimen (P < .001).

An international phase III trial (the FORUM study) conducted between 2013 and 2018 enrolled 417 pediatric patients aged 4 to 21 years with ALL. Patients were randomly assigned to receive either TBI (12 Gy) with etoposide or chemotherapy only (fludarabine, thiotepa, and busulfan or treosulfan) as a preparative regimen. All patients were in morphological CR at the time of transplant and received a 9/10 or 10/10 matched sibling donor (MSD) or unrelated matched donor (URD) transplant. The intent was to enroll 1,000 patients, but the study was closed to enrollment early when a futility early stopping rule was met, indicating that the chemotherapy-only preparative regimen was associated with an inferior outcome.[93]

The 2-year EFS rate was also superior in patients who received TBI (86% vs. 58%, P < .001), primarily because of a lower cumulative incidence of relapse in the TBI cohort (2-year cumulative incidence of relapse, 12% for TBI patients vs. 33% for chemotherapy-only patients).

An international phase III trial (the FORUM study) conducted between 2013 and 2018 enrolled 417 pediatric patients aged 4 to 21 years with ALL. Patients were randomly assigned to receive either TBI (12 Gy) with etoposide or chemotherapy only (fludarabine, thiotepa, and busulfan or treosulfan) as a preparative regimen. All patients were in morphological CR at the time of transplant and received a 9/10 or 10/10 matched sibling donor (MSD) or unrelated matched donor (URD) transplant. The intent was to enroll 1,000 patients, but the study was closed to enrollment early when a futility early stopping rule was met, indicating that the chemotherapy-only preparative regimen was associated with an inferior outcome.[93]

In subgroup analysis, the TBI regimen was superior regardless of donor type (MSD vs. URD), immunophenotype (B-ALL vs. T-ALL), and whether transplant occurred in first CR or second CR.

An international phase III trial (the FORUM study) conducted between 2013 and 2018 enrolled 417 pediatric patients aged 4 to 21 years with ALL. Patients were randomly assigned to receive either TBI (12 Gy) with etoposide or chemotherapy only (fludarabine, thiotepa, and busulfan or treosulfan) as a preparative regimen. All patients were in morphological CR at the time of transplant and received a 9/10 or 10/10 matched sibling donor (MSD) or unrelated matched donor (URD) transplant. The intent was to enroll 1,000 patients, but the study was closed to enrollment early when a futility early stopping rule was met, indicating that the chemotherapy-only preparative regimen was associated with an inferior outcome.[93]

There was no difference in the rates of acute or chronic GVHD or frequency of grades 3 or 4 nonhematologic adverse events between the two randomized treatment arms.

A substudy of the FORUM trial compared two chemotherapy preparative regimens (busulfan/thiotepa/fludarabine with treosulfan/thiotepa/fludarabine) in 191 children (aged <4 years) who were nonrandomly assigned to non-TBI regimens. The two regimens were also nonrandomly assigned by center/country preference, as some countries did not have access to treosulfan.[94]

A substudy of the FORUM trial compared two chemotherapy preparative regimens (busulfan/thiotepa/fludarabine with treosulfan/thiotepa/fludarabine) in 191 children (aged <4 years) who were nonrandomly assigned to non-TBI regimens. The two regimens were also nonrandomly assigned by center/country preference, as some countries did not have access to treosulfan.[94]

The 3-year probabilities of EFS and OS were 0.52 (95% CI, 0.44–0.59) and 0.69 (95% CI, 0.61–0.76), respectively.

A substudy of the FORUM trial compared two chemotherapy preparative regimens (busulfan/thiotepa/fludarabine with treosulfan/thiotepa/fludarabine) in 191 children (aged <4 years) who were nonrandomly assigned to non-TBI regimens. The two regimens were also nonrandomly assigned by center/country preference, as some countries did not have access to treosulfan.[94]

Multivariate analysis showed no difference in EFS and OS according to preparative regimen used, but decreased OS for patients with KMT2A rearrangements and lower EFS in children younger than 1 year at diagnosis.

A substudy of the FORUM trial compared two chemotherapy preparative regimens (busulfan/thiotepa/fludarabine with treosulfan/thiotepa/fludarabine) in 191 children (aged <4 years) who were nonrandomly assigned to non-TBI regimens. The two regimens were also nonrandomly assigned by center/country preference, as some countries did not have access to treosulfan.[94]

A historical comparison was conducted between patients aged 2 to 4 years in this trial and patients aged 2 to 4 years who received TBI regimens in two previous international studies performed by the same group. In the ALL-SCT BFM 2003 trial, 3-year probabilities of EFS and OS were 0.83 (95% CI, 0.66–0.92) and 0.91 (95% CI, 0.76–0.97), respectively. In the ALL-SCT BFM International trial, the 3-year probabilities of EFS and OS were 0.87 (95% CI, 0.57–0.97) and 0.93 (95% CI, 0.61–0.99), respectively. In the FORUM trial, the 3-year probabilities of EFS and OS for children who received either chemotherapeutic conditioning regimen were 0.55 (95% CI, 0.44–0.64) and 0.68 (95% CI, 0.57–0.76), respectively (P = .007 and P = .008 for comparison with the TBI-based trials, respectively).

A substudy of the FORUM trial compared two chemotherapy preparative regimens (busulfan/thiotepa/fludarabine with treosulfan/thiotepa/fludarabine) in 191 children (aged <4 years) who were nonrandomly assigned to non-TBI regimens. The two regimens were also nonrandomly assigned by center/country preference, as some countries did not have access to treosulfan.[94]

The authors concluded that there is strong evidence that TBI-based regimens are superior in children older than 2 years, and this result should be considered as parents and clinicians evaluate the risks and benefits of TBI in children aged 2 to 4 years.