Lower leukemia burden maximizes the impact of blinatumomab therapy

Blinatumomab was the first bispecific antibody‐derived therapy to be approved for use in the United States and other countries around the world. Blinatumomab consists of an CD19‐targeting single‐chain variable fragment (scFv) linked to a CD3‐targeting scFv and thus functions to physically approximate CD19‐expressing leukemia blasts in acute lymphoblastic leukemia with CD3‐expressing T lymphocytes with cytotoxic potential, leading to immunologic destruction of the leukemia blasts. Blinatumomab has followed a very unique developmental path, having first been studied in Philadelphia chromosome (Ph)‐negative B‐cell acute lymphoblastic leukemia (B‐ALL) in low burden disease in a pilot study of 21 patients with measurable residual disease (MRD), where it was shown to be associated with an 80% response rate. The early promise of this approach led to the phase 2 BLAST study to assess MRD conversion in a larger patient sample. Before the completion of the BLAST study, blinatumomab was studied as a single agent for relapsed/refractory (R/R) Ph‐ negative B‐ALL in the phase 3 TOWER randomized controlled trial. In TOWER, the overall response rate (complete remission with full [CR], partial [CRh], or incomplete [CRi] hematologic recovery included) was 43.9% with 33.6% achieving CR with full hematologic recovery among the 271 patients who were randomized to receive blinatumomab instead of conventional chemotherapy. In a pre‐ specified subgroup analysis, there was a suggestion of lower likelihood of response in those with high blast burden (>50% marrow blasts), with a hazard ratio (HR) of 1.99 (1.12–3.55) in favor of response in the high burden group when compared with conventional chemotherapy versus 3.65 (1.63–8.17) in the lower burden group. Notably, when the BLAST study was ultimately fully accrued and reported (after the TOWER study was reported) the outcomes of 113 evaluable patients showed the response rate, as measured by conversion from MRD positivity at >10−3 to MRD negative <10−4 (i.e., at least a one‐log reduction) was 78%, consistent with results from the phase 1 study. Given that MRD and relapsed disease lie on a spectrum of leukemia burden, the aforementioned early studies with blinatumomab made evident that this immunotherapy has more impact and higher response rates at lower leukemia burdens. In the present issue, Queudeville et al. pooled data from five trials in which blinatumomab was employed as a single agent for R/R B‐ALL. They categorized patients in three groups: group 1 with ≥50% marrow blasts, group 2 with ≥25% to <50% marrow blasts, and group 3 with ≥5% to <25% marrow blasts. A total of 683 patients (166 pediatric and 517 adult) were included, among whom the median blasts burden was 77%, with 461 in group 1, 104 in group 2, and 118 in group 3. When comparing group 1 with the lower blast burden patients (222 for groups 2 and 3 combined), the lower burden patients had significantly higher overall and event‐free survival. Patients in groups 2 and 3 had 37% and 46% lower risk of death, respectively, when compared with group 1, and the response rate (CR/CRh/CRi) was 65% in those with <50% blasts compared with 38% in those with ≥50% blasts. Importantly, the authors found no significant differences groups 2 and 3 in the likelihood of response, MRD response, risk of death, or event‐free survival. This pooled study analysis from Queudeville et al. reinforces the original suggestion from the TOWER study of reduced likelihood of response and higher risk of death in those treated with blinatumomab with >50% marrow blast burden. Reassuringly, it also is consistent with real‐world experience using blinatumomab in R/R Ph‐negative B‐ALL reported by Badar el al. In a retrospective study of 276 patients treated with blinatumomab at multiple centers, the response rate (CR/CRi) was 65% and blinatumomab was found to be used outside of clinical trials for R/R B‐ALL in patients with median marrow blast burden of 40% (i.e., lower than the median leukemia burden in the studies evaluated by Queudeville et al.). This suggests there is likely already an element of patient selection in the real world with preference for using blinatumomab at lower leukemia burden to achieve higher likelihood of response and improved patient survival. What remains uncertain is whether interventions to debulk leukemia cells before implementation of blinatumomab can uniformly improve response rates and survival. Queudeville et al. report that 44 patients in one study in their pooled analysis received pre‐phase dexamethasone (10–24 mg/m/day for up to 5 days) for indications of marrow blasts >50%, peripheral blast count ≥15,000 cells/μL, or elevated lactate dehydrogenase at the discretion of investigators and had data available assessing bone marrow blast burden after the pre‐ phase treatment. Dexamethasone debulking was associated with a decreased marrow blast burden from 78.7% to 63.6% (p = .001) and dropped to <50% in nine patients, among whom seven (77.8%) achieved complete remission. These data are not sufficient to recommend routine use of dexamethasone debulking as an optimal approach, and, in fact, can be deemed inadequate if only nine patients experienced a decline in marrow blasts burden to <50% and the median blast burden in those receiving pre‐phase dexamethasone remained >50%. Additionally, 97 patients in the referenced study received dexamethasone pre‐phase therapy, but only 44 were evaluable for marrow response to the pre‐phase therapy. As originally reported for the 97 patients receiving dexamethasone pre‐ phase, there was no impact on overall response rates. Additional