FDA Grants Full Approval to Blinatumomab for MRD+ B-cell Precursor ALL

FDA

The FDA has granted regular approval to blinatumomab (Blincyto) for the treatment of adult and pediatric patients with CD19-positive B-cell precursor acute lymphoblastic leukemia (B-ALL) in first or second complete remission (CR1, CR2) with minimal residual disease (MRD) of at least 0.1%.¹

The agent was initially granted an accelerated approval in March 2018 based on data from the single-arm BLAST trial (NCT01207388), which showed that the 18-month relapse-free survival (RFS) rate was 56% in efficacy-evaluable patients (n = 87), with an estimated median RFS of 22.3 months.^2,3 Moreover, 81.4% of patients (95% CI, 71.6%-89.0%) achieved undetectable MRD.

In the evaluable patients who were in CR1 (n = 61), complete MRD response was observed in 85.2% of patients (95% CI, 73.8%-93.0%); the median hematological RFS was 35.2 months (range, 0.4-53.5). In the patients who were in CR2 (n = 25), the complete MRD response rate was 72.0% (95% CI, 50.6%-87.9%) and the median hematological RFS was 12.3 months (range, 0.7-42.3).

The conversion from an accelerated approval to a full approval was supported by additional findings from two phase 3 studies.

"We are pleased the FDA has granted full approval for [blinatumomab], the first FDA-approved CD19-directed CD3 T-cell engager BiTE immunotherapy and the first to be FDA-approved for MRD in 2018," David M. Reese, MD, executive vice president of Research and Development at Amgen, stated in a press release. "Today's full approval underscores the clinical benefit of [blinatumomab] for people living with B-ALL, and we look forward to exploring how we can continue to make a significant impact for these patients."

BLAST

The open-label, multicenter, single-arm trial enrolled patients with B-ALL who were 18 years of age or older, previously received at least 3 chemotherapy blocks of standard treatment, were in hematologic CR and who had MRD at a level of 0.1% or higher per an assay that has a minimum sensitivity of 0.01%.

Study participants received intravenous blinatumomab at a constant dose of 15 mcg/m² daily, which equates to the recommended daily dose of 28 mcg. They received up to 4 cycles of treatment. Dose adjustments were permitted in the event of toxicities.

A total of 86 patients in CR1 or CR2 received treatment, with a median number of cycles of 2 (range, 1-4). After blinatumomab was administered, 73.8% of those in CR1 and 56.0% of those in CR2 received allogeneic hematopoietic stem cell transplant (HSCT) in continuous hematologic CR.

The median age of patients was 43 years (range, 18-76), with 12% aged 65 years or older. Slightly more than half (58%) of patients were male, and most patients (88%) were White and had Philadelphia chromosom– negative disease (99%). Regarding relapse history, 71% were in first CR and 29% were in second CR. Most patients had a MRD level of ≥0.1% and <1% at baseline (52%), followed by ≥1% and <10% (40%), and ≥10% (8%).

To evaluate the efficacy of the agent, investigators assessed achievement of MRD undetectability within 1 cycle of treatment and hematological RFS.

ECOG-ACRIN E1910

The phase 3 ECOG-ACRIN E1910 trial enrolled patients with Philadelphia chromosome–negative disease who were between the ages of 30 years and 70 years.⁴

Patients received 2.5 months of chemotherapy in the form of a BFM-like regimen adapted from the E2993/UKALLXII clinical trial (NCT02660762). Those who had CR or CR with incomplete hematologic recovery (CRi) received central nervous system intensification with high-dose methotrexate and pegaspargase.

Participants (n = 488) were randomly assigned 1:1 to receive 4 cycles of chemotherapy with or without four 28-day cycles of blinatumomab followed by POMP maintenance given for 2.5 years from the start of intensification.

Stratification factors included age (< 55 years vs ≥ 55 years), CD20 status (positive vs negative), rituximab (Rituxan) use (yes vs no), and HSCT intent (yes vs no).

MRD status was identified using 6 color flow cytometry.

Among the 488 patients who were enrolled, the median age was 51 years, and the CR/CRi rate following induction treatment was 81%. A total of 224 patients with MRD negativity underwent randomization, with 112 patients in each arm. A total of 22 patients in each arm went on to undergo allogeneic HCT. Those with MRD positivity were no longer randomized following the March 2018 approval of the agent, but they were assigned to arm C, which received blinatumomab plus chemotherapy.

Data originally presented at the 2022 ASH Annual Meeting showed that in those with MRD negativity, the median overall survival (OS) was not yet reached with blinatumomab plus chemotherapy compared with 71.4 months with chemotherapy alone (HR, 0.42; 95% CI, 0.24-0.75; log-rank P = .003).

When broken down by age, in those under 55 years, the median OS had not yet been reached in either arm (HR, 0.18; 95% CI, 0.06-0.52; P < .001). In those aged 55 years or older, the median OS in the blinatumomab arm was not reached vs 71.4 months with chemotherapy (HR, 0.77; 95% CI, 0.37-1.58; P = .47).

Notably, those with undetectable MRD had improved OS with blinatumomab (HR, 0.51; 95% CI, 0.27-0.97; P = .038) and those with MRD between undetectable and 0.01% also derived survival benefit from the agent (HR, 0.35; 95% CI, 0.06-1.94; P = .16), although it was determined that the numbers were too small to showcase a definitive effect.

References

1. FDA grants full approval for Blincyto (blinatumomab) to treat minimal residual disease-positive B-cell precursor acute lymphoblastic leukemia. News release. Amgen. June 21, 2023. Accessed June 21, 2023. https://www.amgen.com/newsroom/press-releases/2023/06/fda-grants-full-approval-for-blincyto-blinatumomab-to-treat-minimal-residual-diseasepositive-bcell-precursor-acute-lymphoblastic-leukemia
2. Blincyto (blinatumomab). Prescribing information; Amgen. Accessed June 21, 2023. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf
3. FDA expands approval of Blincyto for treatment of a type of leukemia in patients who have a certain risk factor for relapse. FDA. March 29, 2018. Accessed June 21, 2023. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-blincyto-treatment-type-leukemia-patients-who-have-certain-risk-factor-relapse
4. Litzow M, Sun Z, Mattison R, et al. Consolidation with blinatumomab improves overall and relapse-free survival in patients with newly diagnosed B-cell acute lymphoblastic leukemia: impact of age and MRD level in ECOG-ACRIN E1910. Presented at: 2023 EHA Annual Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S115.