David M. Reese, MD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of blinatumomab (Blincyto) for the treatment of adult patients with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have minimal residual disease (MRD) of at least 0.1%.UPDATE 1/22/2019: Blinatumomab Approved in Europe for MRD+ ALL
The indication is specifically for patients with Philadelphia chromosome negative (Ph-), CD19-positive B-cell precursor ALL who are in first or second complete remission (CR). The application for this indication is based on the phase II BLAST study, in which blinatumomab induced a nearly 80% complete MRD response rate in patients with MRD-positive ALL in hematologic CR.
The CHMP recommendation will now be reviewed for a final approval decision by the European Commission. Blinatumomab is currently approved in the EU for adult and pediatric patients with relapsed or refractory Ph-/CD19+ B-cell precursor ALL.
"The continued acknowledgment of MRD status as an approvable endpoint is an important step in the larger paradigm shift of ALL management as early intervention within the ALL treatment continuum has been shown to be an important step in eliminating dangerous detectable disease," David M. Reese, MD, executive vice president of Research and Development at Amgen, the manufacturer of blinatumomab, said in a statement.
"We appreciate the efforts undertaken by the ALL community to work with regulators and other decision makers on the role of MRD in recurrence of disease and look forward to a final decision by the European Commission," added Reese.
BLAST was a single-arm trial of up to 4 cycles of blinatumomab for treatment of patients with B-cell precursor ALL in CR or CR with partial platelet recovery and MRD >0.1%. The primary efficacy endpoint of BLAST was complete MRD response, defined as absence of detectable MRD using an assay with a sensitivity <0.01% after 1 cycle of blinatumomab.
Of 116 patients who received at least one dose of blinatumomab, 87 were in CR with hematologic recovery and baseline MRD >0.1%, including 61 patients in CR1, 25 in CR2 and 1 in CR3. Sixty-nine patients (79.3%; 95% CI, 70.4%-87.6%) achieved a complete MRD response within the first cycle.
The full analysis set from BLAST included 113 patients who were determined to be MRD-positive based on a measurement of ≥0.1% from an assay with a minimum sensitivity of 0.01% after ≥2 weeks from their last chemotherapy treatment. Among this group, 88 (77.9%; 95% CI, 69.1%-85.1%) achieved MRD CR within the first cycle.
Using the 87-patient efficacy analysis set, the 18-month relapse-free survival (RFS) rate was 56%, and the estimated median RFS was 22.3 months. The estimated median RFS time in first CR at the time of treatment with blinatumomab was 25.6 months (95% CI, 18.7-not applicable), median RFS time in the second or third CR was 11.0 months (95% CI, 6.8-15.4). RFS time was numerically longer for patients in CR1 than for those in the second or third CR.
The estimated median RFS time was 23.6 months (95% CI, 17.4-not applicable) for patients with a complete MRD response and 5.7 months (95% CI, 1.6-13.6) for the MRD-nonresponders.
A propensity score analysis for the patients in first remission with or without hematopoietic recovery in BLAST and in Study 20120148—a retrospective cohort study investigating the hematological RFS and overall survival (OS) in adult patients with Ph-negative BCP ALL in hematological CR with MRD—demonstrated that the RFS for the patients treated with blinatumomab was significantly greater than in the historical controls (35.2 vs 8.3 months; log-rank P
The estimated median RFS time with propensity score weighted analyses was 35.18 months (95% CI, 24.2 to not estimable) for the blinatumomab group and 8.3 months (95% CI, 6.23-11.90) for the control group.
Data from the safety population of 137 patients treated with blinatumomab for MRD-positive ALL came from BLAST and the MT103-202, an exploratory, proof-of-concept, multicenter, open-label, single-arm trial of blinatumomab for patients in first complete hematologic remission with MRD-positive B-cell ALL.
The safety profile for blinatumomab in this setting was similar to what has been demonstrated with the treatment in patients with relapsed/refractory ALL. The median treatment exposure for the 137 patients was 55 days (range, 1-196). Ninety-one percent of patients had fever, 69% had a neurological toxicity, 7% had cytokine release syndrome, and 2% had sepsis.
Fatal adverse events occurred in 3 patients: fatal atypical pneumonia within 30 days of starting treatment; subdural hemorrhage at the site of a prior hemorrhage <30 days after the last dose of blinatumomab; and sepsis.
The FDA approved blinatumomab in March 2018 for adult and pediatric patients with MRD-positive ALL. Blinatumomab is also approved in the United States for the treatment of adult and pediatric patients with relapsed or refractory B-cell precursor ALL.
FDA Briefing Document Oncologic Drugs Advisory Committee Meeting BLA 125557 S-013 Blincyto (blinatumomab) Applicant: Amgen, Inc. Published Accessed March 29, 2018. http://bit.ly/2oV6FOq?rel=0" .