Blinatumomab in Relapsed/Refractory Acute Lymphoblastic Leukemia
Although more than 80% of adults with acute lymphoblastic leukemia (ALL) respond to induction chemotherapy with complete clinical remission, up to 50% of these patients relapse with chemoresistant disease.1 Thus, despite the 40% to 50% overall survival (OS) rate that has been reached over the past 10 years, relapsed/refractory leukemia continues to be a clinical challenge.2
Like immune checkpoint inhibitors, such as ipilimumab and nivolumab, bispecific single-chain antibodies act using mechanisms that are independent from small-molecule therapeutics and conventional monoclonal antibodies.3 Specifically, blinatumomab, an investigational bispecific T-cell engaging antibody, directs cytotoxic T-cells to target cells that express CD19. CD19 is expressed in virtually all B-lineage ALL cells and throughout B-cell development.4 This agent has shown antileukemia activity in an exploratory study in adults with relapsed/refractory B-precursor ALL (r/r ALL).5
Topp and colleagues reported the efficacy and toxicity of blinatumomab in a large confirmatory phase 2 study (ASCO 2014; Abstract 7005). This open-label, single-arm, multicenter phase 2 study was conducted in patients with Philadelphia-negative r/r ALL who had relapsed within 12 months of initial therapy. Blinatumomab was given by continuous intravenous infusion for 4 weeks, followed by a 2-week “holiday,” such that each treatment cycle is 6 weeks. A maximum of 5 cycles was given. Of note, blinatumomab dosing was lower in the first week of the first cycle (9 mcg/day on days 1-7), after which blinatumomab was given at a dose of 28 mcg/day. The primary endpoint of the study was complete remission (CR) or CR with partial hematologic recovery (CRh*) within the first 2 cycles.
This study enrolled 189 r/r ALL patients whose median age was 39 years (range, 18-79). Compared with the initial study of blinatumomab, these patients had a higher burden of disease based on blood marrow blood count. These patients received blinatumomab for a median of 2 cycles (range, 1-5).
Among these 189 patients, the response rate (CR + CRh*) to blinatumomab was 43%, with 80% of responses occurring within the first cycle. Median relapse-free survival (RFS) was 5.9 months, and median OS was 6.1 months. CRs/CRh* were seen in all patient subgroups (Table). Thirty-two of 81 patients who were eligible for stem cell transplant (40%) were able to undergo the procedure.
Regardless of causality, the most frequent adverse events (AEs) associated with blinatumomab in r/r ALL were pyrexia, headache, and febrile neutropenia. These events were consistent with prior trials of blinatumomab. The most frequent grade 3/4/5 AEs included febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Two percent of patients had grade 3/4/5 cytokine release syndrome. The most common grade 3/4/5 nervous system disorders were headache, encephalopathy, and ataxia. Twenty-eight (15%) patients had grade 5 AEs, including sepsis and candida infection. Fatal events were only observed in patients with uncontrolled ALL.
Dr Topp concluded that this large phase 2 study confirmed the antileukemia activity of single-agent blinatumomab in a difficult-to-treat population with Philadelphia-negative r/r B-cell ALL. A randomized, open-label, phase 3 study of blinatumomab in this patient population is under way. The extent to which blinatumomab can serve as a bridge to transplant for patients with chemoresistant B-cell ALL is of specific interest in future studies.
1. Gökbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46:64-75.
2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950.
3. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell–engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29(18):2493-2498.
4. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood. 2003;101:1637-1644.
5. Topp MS, Gökbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120(26):5185-5187.