The recently published ECOG-ACRIN Cancer Research Group E1910 trial has transformed the treatment landscape for adults with B-cell acute lymphoblastic leukemia (B-ALL) by demonstrating that blinatumomab improves overall survival (OS) in adults with B-ALL in complete remission (CR), without detectable measurable residual disease (MRD) after initial chemotherapy. This trial cements the role of immunotherapy as part of initial treatment for adults with B-ALL, a milestone that highlights a sensational acceleration in discovery and clinical investigation for this disease.
The phase III multinational E1910 clinical trial was designed to assess the potential improvement in OS associated with the incorporation of blinatumomab, a CD3/CD19 bispecific T-cell engager previously approved to treat relapsed and refractory B-ALL, into chemotherapy-based consolidation therapy. Between 2013 and 2019, 488 adults aged 30-70 with newly diagnosed Philadelphia chromosome-negative (Ph-) B-ALL were enrolled in the study. Following two courses of intensive conventional chemotherapy, 224 patients (median age, 51 years; 50% women) achieved an MRD-negative complete response (CR) — defined as less than 0.01% leukemic cells in the bone marrow by flow cytometry — and were randomized to receive consolidation with either blinatumomab plus chemotherapy or chemotherapy alone. (Early in the study, after the U.S. Food and Drug Administration [FDA] approved blinatumomab for MRD-positive B-ALL, patients achieving CR with persistent MRD were removed from randomization and assigned to the blinatumomab plus chemotherapy arm.)
At the third efficacy interim analysis (median follow-up, 43 months), the primary trial endpoint was met: the addition of blinatumomab to chemotherapy improved three-year OS by 85% compared to 68% for chemotherapy alone (hazard ratio [HR] = 0.41; 95% CI 0.23-0.73; p=0.002). Relapse-free survival was also improved in the blinatumomab plus chemotherapy arm (HR=0.53; 95% CI 0.32-0.87). Further, the addition of blinatumomab was well-tolerated, with grade 3-5, treatment-related neurologic or psychiatric adverse events more common in the blinatumomab arm than in the arm receiving chemotherapy alone (23% vs. 5%, p<0.002). Based on these results, the FDA in June approved blinatumomab as consolidation therapy for CD19-positive, Ph- B-ALL, regardless of MRD status. For adults diagnosed with ALL, as well as their physicians, this is tremendous news. For hematologists caring for patients with ALL, the results also bring added complexity to clinical practice and raise new questions about how to optimize the use of blinatumomab in B-ALL.
What is the preferred backbone regimen?
While most clinicians do not routinely use the E1910 chemotherapy backbone (based on the E2993 regimen), it is logical that blinatumomab may be beneficial in combination with other chemotherapy backbones as has been demonstrated with hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyperCVAD) and is being studied in several ongoing phase II and III trials.
When should blinatumomab be incorporated?
Only 224 of the original 488 enrolled patients “made it” to randomization; more than half (264 patients) did not undergo randomization, most commonly due to refractory or relapsed disease. This suggests that many adults with B-ALL have inherently chemotherapy-resistant leukemia and would benefit from early exposure to blinatumomab, perhaps subverting impending treatment failure. Studies are underway investigating blinatumomab as part of earlier induction therapy.
With the efficacy of blinatumomab established, is there opportunity to replace multi-agent chemotherapy with this new treatment, or to decrease chemotherapy without compromising outcomes?
E1910 added blinatumomab to a full course of conventional chemotherapy (seven chemotherapy blocks plus maintenance), with well-known toxic effects in older adults. Substantial attrition of patients during the study due to toxicity argues for earlier blinatumomab and less chemotherapy.
Does blinatumomab have benefit in the absence of detectable leukemia?
MRD assessment in E1910 was based on flow cytometry with a sensitivity of 0.01%. Whether patients who respond optimally to chemotherapy derive benefit from blinatumomab consolidation is unknown, though generally the literature suggests that the blinatumomab effect is bigger, with less leukemia. (Optimal response is achieving MRD negativity as assessed by newer next-generation sequencing technologies with sensitivity to less than 10-6.)
In Brief
Many questions remain, with ongoing studies already generating more questions. (How should blinatumomab be combined with other novel agents such as inotuzumab? What about subcutaneous blinatumomab?) However, perfection should not be the enemy of the really good. Adults with Ph- B-ALL diagnosed in the post-E1910 era should — whenever possible — be offered participation in an ongoing trial. If a trial is not available or preferred by the patient, incorporation of four courses of blinatumomab into a chemotherapy-based consolidation is supported by E1910. In the years to come, there will be more clarity about how best to use blinatumomab — and, undoubtedly, much more to learn. In summary, E1910 demonstrates the immense value of randomized clinical trials in adult ALL and establishes the role of adding blinatumomab to chemotherapy during consolidation for B-ALL.
Disclosure Statement
Drs. Luskin and Muffly indicated no relevant conflicts of interest.
