Blinatumomab Significantly Prolongs EFS in Pediatric Relapsed B-ALL

Treatment with 1 cycle of blinatumomab (Blincyto) prior to transplant was found to result in a significant improvement in event-free survival (EFS) vs standard intensive multidrug chemotherapy in pediatric patients with high-risk, first-relapse B-cell acute lymphoblastic leukemia (B-ALL), according to results from a phase 3 trial (NCT02393859) published in JAMA.¹

Results showed that at a median follow-up of 22.4 months, events were reported in 31.5% (n = 17/54) of patients who received blinatumomab vs 57.4% (n = 31/54) of those who received chemotherapy. The hazard ratio (HR) for EFS favored blinatumomab (HR, 0.33; 95% CI, 0.18-0.61). The 24-month Kaplan-Meier estimated EFS rates in the investigative and control arms were 66.2% (95% CI, 50.1%-78.2%) and 27.1% (95% CI, 13.2%-43.0%), respectively.

“In this randomized clinical trial in children with high-risk first-relapse B-ALL, 1 cycle of blinatumomab as the third consolidation block before allogeneic hematopoietic stem cell transplant was associated with improved event-free survival [EFS] and lower risk of leukemia recurrence compared with consolidation chemotherapy,” authors of the study wrote.

In the multicenter phase 3 trial, investigators set out to compare blinatumomab vs intensive multidrug consolidation chemotherapy as the third consolidation block prior to allogeneic hematopoietic stem cell transplant in pediatric patients with high-risk, first-relapse B-ALL.

To be eligible for enrollment, patients had to be older than 28 days and younger than 18 years and have Philadelphia chromosome–negative, high-risk, first-relapse B-ALL. They needed to have M1 marrow or M2 marrow at the time of randomization. Only those who had completed induction and the first 2 cycles of standard consolidation therapy were permitted for inclusion. If patients were refractory to induction or relapsed during the first 2 blocks of chemotherapy, they were excluded.

Study participants were randomized 1:1 to receive a third consolidation course with either blinatumomab at a daily dose of 15 μg/m2 for 4 weeks or consolidation chemotherapy per the IntReALL HR 2010 protocol. Patients in the investigative arm were given dexamethasone at 5 mg/m2 prior to treatment on day 1 to avoid first-dose toxicities.

Patients were stratified by age (1 to 9 years and other) and bone marrow/minimal residual disease (MRD) categories (M1 with MRD level of 10-3 or higher, M1 with MRD level of less than 10-3, and M2). At the end of each induction course, MRD status was evaluated. At the end of second consolidation course, investigators assessed cytomorphologic bone marrow status.

The primary end point of the trial was EFS, while a key secondary end point was overall survival (OS). Other secondary end points included cumulative incidence of relapse, MRD remission at end of treatment, survival status of 100 days following transplant, and incidence of toxicities. An exploratory end point of the trial was CD19 status at the time of relapse.

A total of 108 patients underwent randomization on the trial; 54 received blinatumomab, while 54 were given consolidation chemotherapy. All patients randomized to blinatumomab received cycle 1 of treatment, while 94.4% (n = 51/54) of patients on the chemotherapy arm received treatment.

Six patients on the control arm were given blinatumomab prior to transplant; 5 of these patients received blinatumomab following a relapse event after consolidation chemotherapy. Two participants in the investigative arm and none in the control arm were still receiving treatment at the time of the analysis.

The baseline characteristics between the 2 arms proved to be similar, with the exception that more patients who received consolidative chemotherapy were female vs those who received blinatumomab, at 59.3% vs 44.4%, respectively. The majority of patients were White and not Hispanic or Latino. At least half of patients on both arms had a B-cell precursor subtype of common ALL.

Additional data showed that at a median follow-up of 19.5 months, 14.8% of patients in the blinatumomab arm and 29.6% in the consolidation chemotherapy arm had died. The HR for OS from a stratified Cox proportional hazard model was 0.43 (95% CI, 0.18-1.01).

Moreover, MRD remission per polymerase chain reaction was reported in 90% of those on the investigative arm (n = 44/49) vs 54% of those on the control arm (n = 26/48; absolute age difference, 35.6%; 95% CI, 15.6%-52.5%). Eighty-five percent of patients who received blinatumomab and were in MRD remission at baseline remained in remission vs 87% of those who were given consolidation chemotherapy.

Notably, 93% of patients treated with blinatumomab who had detectable MRD at baseline (n = 27/29) achieved MRD remission following treatment vs 24% (n = 6/25) of those treated with consolidation chemotherapy (absolute percentage difference, 69.1%; 95% CI, 45.4%-85.5%). By flow cytometry, MRD remission rates in the investigative and control arms were 90.6% (n = 48/53) and 60.4% (n = 32/53), respectively.

Because patients included on the trial were high risk, the goal was to have all patients achieve a second complete remission (CR) so that they could undergo transplant. Results indicated that 88.9% of those in the investigative arm and 70.4% of those in the control arm underwent transplant while in second continuous CR.

Approximately 24% of patients in the blinatumomab arm and about 54% of patients in the consolidative-chemotherapy arm relapsed; this translated to a stratified HR for cumulative incidence of 0.24 (95% CI, 0.13-0.46). At 24 months, the cumulative incidence relapse rate in the investigative and control arms were 24.9% (95% CI, 13.2%-38.5%) and 70.8% (95% CI, 50.7%-83.9%), respectively.

Regarding safety, all patients on the blinatumomab arm experienced adverse effects (AEs) vs 96.1% of those on the chemotherapy arm. The most frequently reported toxicities in those who received blinatumomab included pyrexia (81.5%), nausea (40.7%), headache (35.2%), and stomatitis (35.2%).

Moreover, 57.4% (n = 31/54) of those in the investigative arm experienced effects that were grade 3 or higher in severity vs 82.4% (n = 42/51) of those in the control arm. The most common grade 3 or higher toxicities comprised thrombocytopenia (18.5%), stomatitis (18.5%), neutropenia (16.7%), and anemia (14.8%).

The incidence of serious AEs in the investigative and control arms was 24.1% and 43.1%, respectively. No fatal toxicities were observed. Two patients who received blinatumomab experienced AEs that resulted in treatment discontinuation.

Reference

1. Locatelli F, Zugmaier G, Rizzari C, 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;325(9):8433-854. doi:10.1001/jama.2021.0987