Total Body Irradiation Plus Etoposide Improves Survival in Select Transplant-Eligible Pediatric High-Risk ALL

Total body irradiation (TBI) plus etoposide prior to hematopoietic stem cell transplantation (HSCT) resulted in improved overall survival (OS) and a lower risk of relapse in pediatric patients with high-risk acute lymphocytic leukemia (ALL) compared with chemotherapy conditioning, according to results from the phase 3 FORUM trial (NCT01949129).¹

After a median follow-up of 2.1 years, patients who received TBI had a significantly higher 2-year probability of OS (0.91; 95% CI, 0.86-0.95) compared with those who underwent chemotherapy conditioning (0.75; 95% CI, 0.67-0.81; P <.0001). Two-year event-free survival (EFS) was also significantly higher in the cohort who received TBI (0.86; 95% CI, 0.79-0.90) compared with the cohort who received chemotherapy conditioning (0.58; 95% CI, 0.50-0.66; P <.0001).

Additionally, the 2-year cumulative incidence of relapse (CIR) was 0.12 (95% CI, 0.08-0.17) in the TBI cohort and 0.33 (95% CI, 0.25-0.40) in the chemotherapy-conditioning cohort (P <.0001). The 2-year cumulative incidence of treatment-related mortality (TRM) in the 2 arms was 0.02 (95% CI, <0.01-0.05) versus 0.09 (95% CI, 0.05-0.14), respectively (P = .0269).

“Pediatric patients with high-risk ALL who received myeloablative TBI plus etoposide prior to HSCT had a significantly better survival and lower relapse risk and TRM versus patients who received myeloablative chemotherapy,” lead study author Christina Peters, MD, of St. Anna Children’s Hospital, Children’s Cancer Research Institute, University of Vienna, and colleagues, wrote in the report.

TBI is commonly used in conditioning regimens for patients with ALL who are undergoing allogeneic HSCT, however novel chemotherapy agents and combinations may offer less acute and late adverse effects (AEs) that may be more detrimental than the risk of disease recurrence.^2-5 Head-to-head, prospective comparisons of chemotherapy conditioning and TBI-based regimens are needed to evaluate differences in disease-free survival (DFS), as well as long-term toxicities.

To this end, investigators launched the prospective, controlled, open-label, phase 3 FORUM study, which was conducted in 88 centers across 21 countries. The primary objective of the trial was to evaluate noninferiority of chemotherapy conditioning compared with TBI relative to OS.

To be eligible for participation, patients needed to have high-risk ALL, have been 18 years of age or younger at their initial diagnosis, and have been between the ages of 4 years and 21 years when they underwent HSCT. They also needed to have an indication for allogeneic HSCT, be in complete morphological remission prior to transplant, and a human leukocyte antigens (HLA)–identical sibling donor (MSD) or HLA-compatible related or unrelated matched donor (MD) that matched 9 or 10 of 10 HLA loci.

If patients had undergone prior HSCT, received cranial radiation before transplant (>18 Gy at any time or >12 Gy in the last 24 months), had pre-existing severe organ toxicities, were pregnant, or had a second malignancy, they were excluded.

The study enrolled a total of 413 participants who were randomized 1:1 to receive either TBI plus 60 mg/kg of intravenous etoposide at 1.8 g/m² with an upper total dose 3.6 g once on day 3 prior to HSCT (n = 212), or 30 mg/m² of intravenous fludarabine once daily over 5 days, 5 mg/kg of thiotepa twice daily for 1 day, and either 14 g/m² of treosulfan once daily for 3 days or busulfan over 4 days (n = 201).

Busulfan was administered once, twice, or 4 times daily depending on local guidelines, age, and body weight. Additionally, TBI was delivered via linear accelerator at 12 Gy in 6 fractions over the course of 3 days with lung shielding at 10 Gy. The administration of prophylaxis for graft-versus-host disease (GVHD) prophylaxis was dependent on the donor type and stem cell source.

The primary end point of the study was OS from random assignment date, with key secondary end points consisting of EFS, CIR, TRM, acute GVHD, chronic GVHD, toxicity at day 100, GVHD-free survival, and RFS.

The majority of the study participants were male (65%). Thirty-four percent of patients were between the ages of 6 years and 10 years, 27% were older than 14 years, 26% were between 10 years and 14 years, and 14% were between 4 years and 6 years. Seventy-two percent of patients had B-cell precursor ALL, while 23% had T-cell ALL, 4% had biphenotypic disease, and 1% had an unknown immunophenotype.

Additionally, most patients received a stem cell donation from an MD (73%) while fewer had an MSD (27%). Eighty-two percent of patients received a bone marrow transplant, 12% received a peripheral blood transplant, and 4% received a cord blood transplant. At baseline, 54% of patients were in their first CR (CR1), 40% were in their second (CR2), and 4% were in their third.

Additional data indicated that patients who received a transplant during CR1 (n = 224) had a 2-year OS of 0.85 (95% CI, 0.79-0.90) and a 2-year EFS of 0.80 (95% CI, 0.73-0.85); both end points were significantly higher in the TBI arm versus the chemotherapy-conditioning arm. Those who received a transplant during CR2 (n = 87) and relapsed more than 30 months following their diagnosis had a 2-year OS and EFS of 0.89 (95% CI, 0.78-0.95) and 0.69 (95% CI, 0.56-0.79), respectively. Again, both end points were found to be substantially higher in the TBI cohort.

Moreover, patients who had a BCR-ABL mutation (n = 30), KMT2A-AFF1 translocation (n = 11), or blast cell hypodiploidy (less than 45 chromosomes; n = 31) and received treatment with TBI had a significantly higher 2-year EFS rate compared with those in the chemotherapy-conditioning arm, at 0.89 (95% CI, 0.71-0.97) versus 0.60 (95% CI, 0.36-0.78; P = .0182), respectively.

Notably, of the TBI, busulfan-containing chemotherapy conditioning, and treosulfan-containing chemotherapy conditioning cohorts, 3.6% (n = 7/194), 7.3% (n = 7/96), and 10.0% (n = 9/90) of patients, respectively, died without relapsing. A total of 67 patients relapsed following HSCT; of these patients, 38 died and 39 received salvage therapy with curative intent.

No unexpected serious AEs were reported. The most common grade 3/4 AEs observed at day 100 across all study arms included cytopenia, mucositis, nausea, and infection.

References

1. Peters C, Dalle JH, Locatelli F, et al. Total body irradiation or chemotherapy conditioning in childhood ALL: a multinational, randomized, noninferiority phase III study. J Clin Oncol. 2020;39(4):295-307. doi:10.1200/JCO.20.02529
2. Friend BD, Bailey-Olson M, Melton A, et al. The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation. Pediatr Blood Cancer. 2020;67(2):e28079. doi:10.1002/pbc.28079
3. Gao RW, Dusenbery KE, Cao Q, et al. Augmenting total body irradiation with a cranial boost before stem cell transplantation protects against post-transplant central nervous system relapse in acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2018;24:501-506. doi:10.1016/j.bbmt.2017.11.013
4. Hill-Kayser CE, Plastaras JP, Tochner Z, et al. TBI during BM and SCT: review of the past, discussion of the present and consideration of future directions. Bone Marrow Transplant. 2011;46:475-484. doi:10.1038/bmt.2010.280
5. Lee JW, Kang HJ, Kim S, et al. Favorable outcome of hematopoietic stem cell transplantation using a targeted once-daily intravenous busulfan-fludarabine-etoposide regimen in pediatric and infant acute lymphoblastic leukemia patients. Biol Blood Marrow Transplant. 2015;21:190-195. doi:10.1016/j.bbmt.2014.09.013