JAMA Interpretation | Professor Shen Shuhong: Consolidation therapy with Bellinto Oumab in children with high-risk first relapse B-ALL significantly prolongs EFS and improves transplant prognosis

Bellintoomab is the world’s first CD3/CD19 bispecific T cell adapter (BiTE@) immunotherapy drug, and it has obtained the FDA’s breakthrough therapeutic drug designation for the treatment of relapsed and refractory (R) in adults and children.
/R) Precursor B-cell acute lymphoblastic leukemia (ALL) and complete remission (CR) with minimal residual disease (MRD) positive precursor B-cell ALL patients.

In December 2020, it was approved by the National Medical Products Administration (NMPA) for use in adult patients with R/R precursor B cell ALL.

Professor Shen Shuhong from Shanghai Children's Medical Center is invited to conduct an in-depth interpretation of the latest research results of belintoomab in children with high-risk first relapse B-cell acute lymphoblastic leukemia (B-ALL).

Professor Shuhong Shen, Doctor of Genetics, Chief Physician, Director of the Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Deputy Director, Institute of Pediatric Translational Medicine, Shanghai Jiaotong University School of Medicine, Secretary General, National Pediatric Leukemia Expert Committee, Chinese Medical Doctor Association Pediatric Branch, Hematology Oncology Specialist The deputy chairman of the committee, the leader of the standardized training of children's hematological tumors by the Shanghai specialists, as the first author or corresponding author, published research articles in JAMA oncology, Nature Genetics, Haematologica, Oncogene and other journals.
EFS risk of first relapse chemotherapy of B-ALL: from a randomized controlled trial of: Franco Locatelli, Gerhard Zugmaier, Carmelo Rizzari, et al Objective at high risk of first relapse in patients with B-ALL children allogeneic hematopoietic stem cell transplantation (allo- Event-free survival (EFS) after the use of belintouximab before HSCT vs.
consolidation chemotherapy as the third course of consolidation treatment.Study Design This randomized controlled phase 3 clinical trial was conducted from November 2015 to July 2019 (data cut-off date, July 17, 2019) and randomly enrolled children with high-risk first relapse B-ALL from 47 centers in 13 countries Patients (age>28 days and <18 years old, morphological CR [bone marrow M1, <5% blasts] or bone marrow M2 [blasts ≥5% and <25%]).

The patients were randomized to receive 1 cycle of belintolumab (n=54; 15μg/m2/d, continuous intravenous infusion for 4 weeks) or chemotherapy (n=54) as the third course of consolidation treatment.

The primary endpoint is EFS (events include: recurrence, death, second malignancy, or failure to achieve complete remission).

The key secondary endpoint is overall survival (OS).

Other secondary endpoints include MRD remission rate and adverse event (AE) rate.

Main research results A total of 108 patients were randomized (median age 5.
0 years; 51.
9% were girls; 97.
2% were bone marrow M1), and all patients were included in the analysis.

Based on the benefits of belintoomab, the study was terminated early in accordance with the pre-set stopping rules.

01EFS Compared with the consolidation chemotherapy group, the EFS of the belintolumab group was significantly prolonged (P<0.
001; HR: 0.
33).

With a median follow-up of 22.
4 months, the incidence of events in the belintolumab group and the consolidation chemotherapy group were 31.
5% and 57.
4%, respectively.

The 24-month EFS rate: 66.
2% vs 27.
1%, P<0.
001 (Figure 1A).

The HR value in all subgroups is favorable to the belintuzumab group.

In the early recurrence (from diagnosis to recurrence <18 months) subgroup, the event incidence rate was 31.
6% in the belintouximab group and 63.
6% in the consolidation chemotherapy group, HR: 0.
21.

Fewer events were observed in the belintougumab group, which was independent of the MRD level at the end of induction or before the start of treatment (Figure 2).

The median follow-up for 02OS was 19.
5 months.
The 24-month OS rate of the Bellintolumab group and the consolidation chemotherapy group was 81.
1% vs 55.
8%, and the HR: 0.
43 (Figure 1B).

03MRD remission rate The MRD remission was assessed by PCR and flow cytometry, which was defined as bone marrow blasts <10-4 within 29 days after the start of treatment.

PCR-assessed MRD remission: Compared with the consolidation chemotherapy group, the MRD remission rate of the belintouximab group was higher (90% vs 54%).

In the subgroup of patients with negative baseline MRD, most patients still maintained MRD remission after treatment (85% vs 87%); among the subgroup of patients with baseline MRD>10-4, the MRD remission rate of belintolumab group Higher (93% vs 24%).

MRD remission assessed by flow cytometry: Similar to the PCR assessment, the MRD remission rate of the belintolumab group was higher (90.
6% vs 60.
4%).

04 Cumulative recurrence rate The 24-month cumulative recurrence rate of the belintolumab group and the consolidation chemotherapy group was 24.
9% vs 70.
8%, and 1 patient in each of the two groups had CD19-negative recurrence (Figure 1C).

05 Allo-HSCT rates are high-risk because the enrolled patients are at high risk.
The purpose of this trial is to allow all patients who have received a second CR to receive allo-HSCT.

Forty-eight patients (88.
9%) in the belintougumab group and 38 patients (70.
4%) in the consolidation chemotherapy group received allo-HSCT after the second CR.

Three patients (6.
3%) in the belintoomab group and 8 patients (21.
1%) in the consolidation chemotherapy group died due to recurrence/disease progression after receiving allo-HSCT.

06 Safety AEs were collected from the start of treatment to 90 or 30 days after allo-HSCT (patients who did not receive allo-HSCT).

No fatal AE was reported.

In the belintoomab group and the consolidation chemotherapy group, the incidence of any AE was 100% and 96.
1%, respectively, the incidence of serious AE was 24.
1% and 43.
1%, and the incidence of grade ≥3 AE was 57.
4% and 57.
4%.
82.
4%; the incidence of neurological events was 48.
1% and 29.
4%, of which there were 3 cases and 1 case of grade 3-4; 2 cases and 1 case of CRS ≥3 grade.

Figure 1.
Efficacy endpoint of belintuomab versus chemotherapy.
Figure 2.
EFS study conclusions of the study subgroup.
In high-risk first-time B-ALL children with B-ALL, use one cycle of belintuomab before allo-HSCT As the third course of consolidation treatment, compared with standard intensive multi-drug chemotherapy, it can improve EFS and reduce the risk of leukemia recurrence.

In patients treated with belintoomab, the risk of disease recurrence is lower and the EFS rate is higher, which is consistent with the improvement of the prognosis of children with ALL transplantation by achieving MRD remission before allo-HSCT.

Therefore, treatment with belintouximab prior to transplantation may be a valuable consolidation treatment that seems to be more effective than conventional chemotherapy.

Experts comment that some trials have demonstrated that low leukemia burden is associated with the treatment response of belintoxumab and improved survival rates.

In this study, patients with MRD remission or low leukemia burden received 1 cycle of belintoux as a late consolidation treatment, and then received allo-HSCT, and the prognosis was improved.

Another COG-AALL1331 study initiated by the National Cancer Institute (NCI) used a single cycle of re-induction chemotherapy for children, adolescents, and young adults (AYA) who had relapsed for the first time and then randomly received 2 cycles of belintoose.
Anti-or 2 cycles of consolidation chemotherapy, followed by allo-HSCT, reached similar conclusions.

These two randomized clinical trials have confirmed that belintoux is a more effective and low-toxicity treatment for children with B-ALL patients who are at high risk for first recurrence and responds to chemotherapy.
In order to evaluate the use of belintoux in children The role of chemotherapy-sensitive leukemia (including newly diagnosed or low-risk first recurrence B-ALL) provides the basis.

Several conclusions can be drawn from the above two studies to support the change in clinical practice: First, the toxicity of belintolumab is significantly less than that of chemotherapy.

In particular, life-threatening complications such as infection and sepsis often lead to delays in receiving HSCT, and these toxicities are not common in belintoomab.

Second, the negative rate of MRD in the belintuomab group was higher than that in the chemotherapy group alone.

This is a critical endpoint because survival outcomes after transplantation are highly dependent on the degree of disease control at the time of transplantation.

Third, for the above reasons, compared with patients who received chemotherapy alone, patients who received belintolumab consolidation therapy were more likely to receive HSCT.

These two studies are the first randomized trials to show that belintoux has a significant benefit in children with high-risk relapse B-ALL.

Due to the improved prognosis and good toxicity, belintolumab and other immunotherapies are supported as the first-line treatment and relapse treatment for childhood ALL in future clinical trials.

References: 1.
Locatelli Franco, et al.
Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
JAMA.
2021 Mar 2;325( 9):843-854.
2.
Brown Patrick A, et al.
Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
JAMA.
2021 Mar 2;325(9):833-842.
3.
Shukla N, Sulis ML.
Blinatumomab for Treatment of Children With High-risk Relapsed B-Cell Acute Lymphoblastic Leukemia.
JAMA.
2021 Mar 2;325(9) :830-832.
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