Page 242 - Haematologica Vol. 110 - January 2025

LETTER TO THE EDITOR
Blinatumomab is associated with better post-transplant outcome than chemotherapy in children with high-risk, first-relapse B-cell acute lymphoblastic leukemia irrespective of the conditioning regimen
Total body irradiation (TBI) is a key component of many con- ditioning regimens administered prior to allogeneic hemato- poietic stem cell transplantation (alloHSCT) in patients with acute lymphoblastic leukemia (ALL). A recent, large random- ized clinical study – FORUM – including patients with a donor matched for ≥9/10 HLA loci demonstrated that children with high-risk/relapsed ALL who received TBI plus etoposide as a conditioning regimen had a significantly higher (P<0.0001) 2-year probability of overall survival (0.91, 95% confidence interval [95% CI]: 0.86-0.95) than that of patients who re- ceived conditioning with chemotherapy (chemoconditioning; 0.75, 95% CI: 0.67-0.81) prior to alloHSCT.1 Although effective, conditioning with TBI is associated with the risk of lifelong adverse effects, including impairment of growth, gonadal, thyroid and cognitive function, an increased incidence of cataracts, and secondary malignancies.2-4 A novel approach aimed at providing an alternative to TBI-based conditioning is, therefore, desirable.
Blinatumomab is a bispecific T-cell engager that redirects CD3-positive T cells to engage and lyse CD19-positive target cells. A randomized, phase III trial (NCT02393859) demon- strated that treatment with one cycle of blinatumomab compared with standard intensive multidrug chemotherapy administered as the third consolidation course (HC3) prior to alloHSCT in pediatric high-risk, first-relapse B-cell ALL (B-ALL) resulted in an improvement in event-free survival and overall survival.5,6 In order to better dissect the contri- bution of immediate pre-transplant treatment from the role played by the conditioning regimen, we performed a post hoc analysis aimed at evaluating the outcome of children with high-risk, first-relapse B-ALL from this phase III study who received either blinatumomab or chemotherapy (HC3) as the third consolidation course and for whom data on the type of conditioning regimen received (TBI or chemoconditioning) prior to alloHSCT were available.
Details of the study design, patients’ eligibility, and treat- ment doses of blinatumomab and HC3 have been reported elsewhere.5 High-risk first relapse has been defined earlier.7,8 Patients who achieved or maintained a second complete remission after treatment with either blinatumomab or HC3 were assigned to receive TBI or chemoconditioning before alloHSCT. Myeloablative conditioning prior to alloHSCT con- sisted of TBI (12 Gy in 6 fractions) plus 60 mg/kg etoposide (1.8 g/m2; maximum total dose 3.6 g) or chemoconditioning including fludarabine (30 mg/m2 once a day for 5 consecutive
days) plus thiotepa (5 mg/kg twice a day for 1 day) and either treosulfan (14 g/m2 once a day for 3 consecutive days) or bu- sulfan.1 Busulfan was dosed once, twice, or four times a day according to local guidelines, age, and body weight, usually with therapeutic drug monitoring and pharmacokinetic dose adjustment. Time-to-event endpoints were summarized us- ing the Kaplan-Meier method. Transplant-emergent adverse events were assessed by the clinicians per good clinical prac- tice guidelines and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Acute and chronic graft-versus-host disease were assessed at each visit and graded according to the descrip- tion by Glucksberg et al.9 The study protocol was approved by the institutional review boards or independent ethics committees of all participating institutions. A Cox regression model was used to evaluate the effects of treatment with either blinatumomab or chemotherapy before alloHSCT and of the conditioning regimen on patients’ outcome.
Of the 90 evaluable patients for whom data on the condi- tioning regimen administered were available, 51 received bli- natumomab and 39 received HC3. Of the 51 patients treated with blinatumomab, 30 patients received TBI plus etoposide and 21 patients received chemoconditioning (5 of 21 patients received fludarabine + thiotepa + treosulfan; 16 of 21 received fludarabine + thiotepa + busulfan prior to alloHSCT). Of the 39 patients given HC3, 19 received TBI and 20 received chemoconditioning (16 patients received the busulfan-based regimen and the remaining 4 had the treosulfan-based preparation) before alloHSCT. The patients’ demographics and baseline characteristics, including measurable residual disease (MRD), were well balanced between the blinatum- omab and HC3 treatment groups prior to administration of TBI or chemoconditioning (Table 1). Fifty percent of patients treated with blinatumomab (25 of 51 patients) and 41% of patients treated with HC3 (16 of 39 patients) received a transplant from matched donors with an HLA match of ≥9/10, this representing the population of children eligible for the randomized trial conducted by the FORUM consortium. The remaining patients were eligible to be reported in the FORUM database. The median time elapsed between the last dose of blinatumomab and alloHSCT was 25 days (range, 8-67 days) and the median time between the last dose of HC3 and alloHSCT was 44 days (range, 20-107 days).
Two of 51 patients (4%) treated with blinatumomab experi- enced cytokine release syndrome. Cyclosporine and meth-
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