Blinatumomab with consolidation chemotherapy prolongs the overall survival of patients with MRD-negative B-Cell ALL
Results of the phase III ECOG-ACRIN E1910 trial, presented as a late breaking abstract during the 2022 annual ASH meeting, show that the addition of blinatumomab to consolidation chemotherapy significantly prolongs the survival of adult patients with newly diagnosed B-lineage ALL without minimal residual disease (MRD) after induction and intensification chemotherapy. Blinatumomab is already approved for patients with MRD-positive B-lineage ALL who are in remission after induction chemotherapy and these data will likely broaden its indication to also include patients with MRD-negativity at that stage.
Background
Adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) can achieve a high rate of complete remission (CR) with conventional chemotherapy. However, many patients will eventually relapse, even after they achieved measurable residual disease (MRD) negativity after induction. Blinatumomab is a bispecific T cell engager that is currently approved for the treatment of patients with relapsed/refractory (R/R) B-lineage ALL and for patients in morphologic CR who are MRD positive after induction therapy. The phase III ECOG-ACRIN E1910 study assessed whether blinatumomab could also benefit patients without detectable MRD after induction, a proportion of patients who generally have a better prognosis.
Study design
In the study at hand, newly diagnosed patients with BCR/ABL1 negative, B-lineage ALL between 30 and 70 years of age were treated with 2.5 months of combination induction chemotherapy consisting of a BFM-like regimen that was adapted from the E2993/UKALLXII clinical trial (step 1). In patients below the age of 55 pegaspargase was added to the therapy, while rituximab was added in patients with CD20 positive tumor cells. If patients were in morphologic complete remission (CR/CRi) after induction, they continued on-study and received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). Subsequently, their remission and MRD status were determined using 6-color flow cytometry, with MRD negativity being defined as <0.01%. All patients were then randomized to receive an additional four cycles of consolidation chemotherapy or two cycles of blinatumomab followed by 3 cycles of consolidation chemotherapy, another 4-week cycle of blinatumomab (i.e., the 3rd cycle of blinatumomab) followed by an additional cycle of chemotherapy and a 4th cycle of blinatumomab (step 3). With this regimen, patients in both arms received the same number of cycles and similar doses of chemotherapy. Following completion of consolidation chemotherapy with or without blinatumomab, patients received an additional 2.5 years of maintenance therapy with the POMP regimen (step 4). Patients were allowed to proceed to an allogeneic hematopoietic cell transplant (HCT) at the discretion of the treating physician which was suggested to be done after the first two cycles of blinatumomab in the blinatumomab arm or at any time following intensification chemotherapy in the control chemo arm. The primary objective of the trial was to compare the overall survival (OS) in MRD-negative patients who received blinatumomab in conjunction with chemotherapy to that of patients who received chemotherapy alone.
Results
The median age of patients in the study was 51 years. After the induction phase, the CR/CRi rate proved to be 81% (75% CR). Of the 488 patients that were enrolled in the study, 286 were randomized in step 3 of the study protocol. Of them 224 proved to be MRD negative, while the remaining 62 patients still had residual disease at that point. Following FDA approval of blinatumomab in MRD-positive patients in March 2018, MRD-positive patients were no longer randomized, but all received the blinatumomab-chemotherapy combination.
In September 2022, the data safety monitoring committee of the trial recommended the release of the trial results given the efficacy of blinatumomab in MRD-negative patients. Results after a median follow-up of 43 months showed that MRD-negative patients who received blinatumomab plus chemotherapy during the consolidation phase had a 58% reduced death risk compared to patients who did not receive blinatumomab (median not reached vs. 71.4 months; HR[95%CI]: 0.42[0.24-0.75]; p= 0.003). OS rates after a median follow-up of 3.5 years were 83% and 65%, respectively. Also in terms of relapse-free survival (RFS), patients receiving blinatumomab did significantly better with a median RFS that was not reached vs. 22.4 months with chemotherapy alone (HR[95%CI]: 0.46[0.27-0.78]; p= 0.004).
The study found no new safety concerns associated with the use of blinatumomab and used 72- and 96- hour infusions in 72% of the patients. These infusion times proved necessary to feasibly conduct the trial.
Conclusions
The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better OS in patients with newly diagnosed B-lineage ALL who were MRD negative after intensification chemotherapy. No significant safety concerns were noted. As such, these findings suggest that blinatumomab, which is already approved for patients with MRD positive B-lineage ALL who are in remission after induction chemotherapy, is in fact safe and effective as a first line therapy for all patients with this cancer type.
Reference
Litzow M, et al. Consolidation Therapy with Blinatumomab Improves Overall Survival in Newly Diagnosed Adult Patients with B-Lineage Acute Lymphoblastic Leukemia in Measurable Residual Disease Negative Remission: Results from the ECOG-ACRIN E1910 Randomized Phase III trial conducted by the NCI National Clinical Trials Network. Presented at ASH 2022; Abstract LBA-1.
