Blinatumomab for MRD-Negative Acute Lymphoblastic Leukemia in Adults

Abstract

Background: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.

Methods: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point.

Results: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group.

Conclusions: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

Figure 1.. Treatment Schema.

If leukemia was present in the central nervous system at diagnosis, methotrexate (at a dose of 12.5 mg, administered intrathecally or by means of an Ommaya reservoir) was to be given twice weekly until blasts were not present in cerebrospinal fluid. If the patient subsequently had a complete remission, a total dose of 1800 cGy of cranial irradiation, administered in 10 daily fractions of 180 cGy per fraction, was to be given during the first cycle of maintenance therapy. Maintenance therapy was planned to continue for 2.5 years from the start of the intensification phase. IU denotes international units.

Figure 2.. Randomization and Treatment Phases.

Shown is the status of patients throughout the course of the trial from initial registration (488 patients), followed by 2.5 months of induction therapy (step 1), along with the numbers and reasons why patients did not proceed to intensification (step 2, which included 333 patients) and the following intensification phase and the numbers and reasons why patients did not proceed to the step 3 registration (which included 286 patients). In step 3, patients were randomly or nonrandomly (after protocol amendment 14) assigned to a trial group. Patients who were positive for measurable residual disease (MRD) who had undergone the initial randomization were all later assigned to the blinatumomab group in the trial. The reasons that patients did not proceed to step 4 maintenance therapy after consolidation therapy are listed.

Figure 3.. Overall Survival According to Trial Group and Clinical and Molecular Features.

Panel A shows the comparison of median overall survival among the MRD-negative patients. The widths of the confidence intervals (shaded areas) were not adjusted for multiplicity and may not be used in place of hypothesis testing. Panel B shows the subgroup analysis of overall survival between the blinatumomab group and the chemotherapy-only group among the MRD-negative patients. The stratification factors of CD20 status and rituximab use were added in protocol addendum 9. The subgroup analysis that was defined according to combined molecular risk was post hoc. The size of the squares is inversely proportional to the standard error of the hazard ratio estimates, and arrows indicate confidence intervals that exceed the graphed space.