Non-Response to Blinatumomab Shows Significant Association With Worse Survival Outcomes in B-ALL

Relapsed and refractory (R/R) pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) who had a non-response to blinatumomab (Blincyto) and a high-disease burden were associated with worse outcomes, according to study results published in the Journal of Clinical Oncology.¹

In a retrospective, multicenter study, of children and young adults who were given CD19 targeting chimeric antigen receptor (CAR) T-cell therapy, either blinatumomab, tisagenlecleucel (tisa-cel; Kymriah), or another murine-based CD19-CAR T-cell therapy available on a clinical trial, 77 of 420 observed patients received prior blinatumomab.

Among the evaluable patients (n = 412) non-responders to blinatumomab had lower complete remission rates at 64.5% (20 out of 31) compared to blinatumomab responders at 92.9% (39 of 42), or even blinatumomab naive patients at 93.5% (317 of 339) (P < .0001). Moreover, non-responders had a worse 6-month event-free survival (EFS) at 27.3% (95% CI, 13.6%-43%) vs those who responded with 66.9% experiencing 6-month EFS (95% CI, 50.6%-78.9%, P < .0001).

“Our data support the notion that blinatumomab may lead to CD19 downregulation,” the researchers wrote explaining their findings. “For patients in whom CD19 expression diminished or changed following blinatumomab, the risk of post-CAR relapse with CD19-negative disease was high.”

Cumulative incidence of relapse (CIR) was higher in patients exposed to blinatumomab that didn’t respond, patients that did respond, and blinatumomab-naïve patients at a 6-month CIR of 52.4% (95% CI, 28.8%-71.5%), 26.2% (95% CI, 13.4%-40.9%), and 18.6% (95% CI, 14.6% -23.1%), respectively.

At a median follow-up of 30.1 months the median EFS, relapse-free survival (RFS), and overall survival (OS) among all patients was 20.8% (14.1%-28.8%), 40.2% (24.9%-non-estimable), and 49.1 (42% -non-estimable) months, respectively, with all outcomes being shorter in patients on blinatumomab. Six-month RFS in patients exposed to blinatumomb was 64.1% (95% CI, 50.4%-74.9%) vs 81.1% (95% CI, 76.3%-85%; P = .02 overall) in treatment-naïve patients.

Researchers also noted that high-disease burden was associated with worse survival outcomes in this patient population.

“Blinatumomab utilization remained an independent factor, further contributing to the adverse impact of disease burden on EFS and RFS but not OS,” the researchers noted when discussing how high-disease burden was associated with worse survival outcomes in this patient population. “High-disease burden pre-CAR further amplified poor outcomes for blinatumomab-exposed non-responders.”

414 patients had pre-CAR CD19 expression analyzed that showed that CD19-dim or partial expression was more common in those patients exposed to blinatumomab than those naïve to treatment at 13.3% vs 6.5% (P = .06), respectively. Five of 8 (62.5%) blinatumomab exposed patients with CD19-dim or partial expression achieved CR compared to 19 out of 20 (95%) blinatumomab-naïve patients (P = .06). Yet, all 5 blinatumomab-exposed patients who had achieved CR had a subsequent CD19-negative relapse. Moreover, the majority of patients experienced relapse or non-response (60.7%).

A greater proportion of patients with low disease burden (60.3%) were CD19-positive at relapse in comparisons to 32.7% with a high-disease burden. Late relapses were also more frequently associated with CD19-positive relapse than those who relapsed early.

Further treatment was also investigated in this patient population. A total of 146 patients were given hematopoietic stem cell transplant (HSCT) after CD19-CAR T-cell therapy after a median 93 days. Two-year OS, measured from day 0 of HSCT treatment, was 8.3% (95% CI, 67.6%-85.8%), while the 2-year EFS and RFS were 70.8% (95% CI, 59.5%-79.5%) and 82.6% (95% CI, 71.1%-89.8%), respectively. Thirteen of 92 (13.4%) patients experienced post-HSCT relapse, and for 2 patients this represented relapse following second HSCT.

“Ultimately, our data inform one of the most vexing unanswered current questions in the clinical management of patients with B-ALL, namely, the impact of sequential CD19 targeting strategies. We found that blinatumomab exposure did not preclude CD19-CAR response,” the researchers concluded. “However, blinatumomab non-responders had lower CR rates with subsequent CD19-CAR and blinatumomab exposure was associated with lower EFS and RFS, particularly for those with high-disease burden.”

_Reference

_{Myers RM, Taraseviciute A, Steinberg SM, et al. Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL. J Clin Oncol. 2022 Mar 20;40(9):932-944. doi: 10.1200/JCO.21.01405}