Blinatumomab is superior to chemotherapy consolidation for children with high-risk B-cell precursor ALL at first relapse

Around 15% of pediatric patients presenting with high-risk (HR) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) will relapse, with prognosis depending on time from diagnosis to first relapse and site of relapse (e.g., central nervous system relapse).¹ Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the standard of care if a second complete morphological remission (CR2) can be achieved, but the risk of mortality and morbidity remains high for these patients.¹ Conventionally, these patients are treated with an induction chemotherapy followed by three cycles of high-risk consolidation chemotherapy, prior to allo-HSCT.

Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD19 on tumor cells and recruits T cells through binding to CD3. The proximity of T cells induces an immunological response resulting in increased cytotoxicity and apoptosis of tumor cells. Blinatumomab has been approved to treat pediatric and adult patients with relapsed and refractory BCP-ALL.

At the 62nd American Society for Hematology (ASH) Annual Meeting and Exposition in December 2020, Franco Locatelli presented findings from an open-label, randomized phase III clinical trial (NCT02393859) comparing outcomes of treatment with blinatumomab versus high-risk consolidation cycle (HC)3 chemotherapy.

Study design

• International, multicenter (103 locations), randomized phase III trial, recruiting between November 2015 and July 2019
• All patients were treated with standard induction, followed by HC1 and HC2 chemotherapy
• After HC2, patients were assessed for response and randomized 1:1 to either blinatumomab (15 µg/m²/day for 4 weeks) or standard HC3
• Variables for stratification included age, as well as marrow and MRD status at the end of HC2

Patient eligibility criteria

• Age > 28 days and < 18 years at the time of informed consent/assent
• First relapse at study entry
• Patients had to be in complete remission (M1, < 5% bone marrow blasts) or partial remission (M2, ≥ 5% to < 25% blasts) at time of randomization
• No central nervous system involvement

Study endpoints

• The primary endpoint was event-free survival (EFS)
• Secondary endpoints included overall survival (OS), cumulative incidence of relapse, minimal residual disease (MRD) remission at end of blinatumomab or HC3 treatment, and incidence of adverse events

Results

Efficacy

The planned number of patients was 202 patients in each group, but early termination (as recommended by data monitoring committee) resulted in the final recruitment of 108 patients, with 54 in each group. Enrolment was terminated early at the point of the interim analysis (50% EFS events) as a benefit was found in patients being treated with blinatumomab. Key patient demographics are shown in Table 1.

Table 1. Patient demographics¹

HC3, high-risk consolidation cycle 3; MRD, measurable residual disease; SD, standard deviation.
Characteristic	Blinatumomab (n = 54)	HC3 (n = 54)
Median age, years (range)	6 (1–17)	5 (1–17)
Male vs female, %	56 vs 44	41 vs 59
Mean (SD) time from diagnosis to relapse, months	21.9 (+/-8.0)	22.8 (+/-12.3)
Extramedullary disease at relapse, %	19	26
MRD < 10-4 at screening, %	46	48

• EFS was significantly better in the blinatumomab arm compared with the HC3 arm (p < 0.001), with events reported for 17 patients in the blinatumomab arm (32%) compared with 31 patients (57%) in the HC3 arm (HR, 0.33; 95% CI, 0.18–0.61)
  • Median EFS was not reached (blinatumomab) vs 7.4 months (HC3)
• Table 2 presents the cumulative incidence of relapse in both arms of the study, with a lower number of patients experiencing relapse in the blinatumomab arm
• This benefit was seen both in patients with early relapse (< 18 months after diagnosis; HR, 0.21; 95% CI, 0.07–0.59) as well as patients relapsing late (18–30 months from diagnosis; HR, 0.43; 95% CI, 0.20–0.95)
• Furthermore, there was a trend towards better OS in patients treated with blinatumomab compared to HC3 (HR, 0.43; 95% CI, 0.18–1.01)

Table 2. Cumulative incidence of relapse after CR2

CI, confidence interval; CIR, cumulative incidence of relapse; CR2, second morphological complete remission; HC3, high-risk consolidation cycle 3.
Group	Blinatumomab (n = 54)	HC3 (n = 53)
Total patients with relapses, n	13	29
CIR at 6 months, % (95% CI)	10.7 (3.9-21.5)	42.1 (27.7-55.8)
CIR at 12 months, % (95% CI)	24.9 (13.3-38.5)	59.3 (43.0-72.6)
CIR at 24 months, % (95% CI)	24.9 (13.2-38.5)	70.8 (50.7-83.9)

With regards to MRD status at end of treatment, 90% of patients treated with blinatumomab achieved MRD remission (by polymerase chain reaction [PCR]), compared with 54% of patients treated with HC3. This difference in MRD remission after treatment was even greater in patients who had a baseline MRD ≥ 10^-4 (93% for blinatumomab vs 24% for HC3). By contrast, no difference was seen in MRD remission for patients with a baseline MRD < 10^-4 (85% for blinatumomab vs 87% for HC3)

Safety

• Blinatumomab was better tolerated, with only 57% of patients experiencing ≥ Grade 3 adverse events compared to 82% with HC3
  • Specifically, blinatumomab caused less hematological and liver toxicity than HC3
• There were no deaths observed during the study
• Due to the low tumor burden at treatment start, no Grade 3 or Grade 4 cytokine release syndrome was seen in either arm
• Although neurotoxicity of any grade was higher in the blinatumomab arm (48% vs 29%), ≥ Grade 3 neurotoxicity was comparably low in both arms (6% for blinatumomab vs 2% for HC3).

Conclusion

The study described here demonstrates that blinatumomab is superior to standard consolidation (HC3) prior to allo-HSCT for children with BCP-ALL in first relapse, providing a new standard‑of-care treatment option for these patients. Furthermore, blinatumomab confers superior EFS, greater MRD negativity prior to allo-HSCT, lower risk of recurrence, and improved OS. In addition, treatment with blinatumomab causes fewer and less severe toxicities.

The results of this study have now been published in the Journal of American Medical Association (JAMA).²