Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL

Abstract

PURPOSE CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.

Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

“…The impact of pre‐LD disease burden has been described in ALL previously, 18,22,23 and seems to hold regardless of the type of CAR‐T cells used. The disease burden was not assessed prior to LD in the ELIANA study, but real‐life data from tisagenlecleucel confirm this observation 24,25 . In our study patients with a high disease burden pre LD were those who failed bridging therapy or declined bridging therapy.…”

“…Also, the activity of CD28‐based CAR‐T cells against tumour cells with a lower antigen density, 14 and potential trogocytosis, 13 may also lead to less CD19‐negative relapses in this cohort. Failure of blinatumomab was seen as a risk factor for CD19‐negative relapse following CD19 CAR‐T cells 25 …”

“…The disease burden was not assessed prior to LD in the ELIANA study, but real-life data from tisagenlecleucel confirm this observation. 24,25 In our study patients with a high disease burden pre LD were those who failed bridging therapy or declined bridging therapy. The response to bridging therapy was previously also associated with improved outcome following CD28-based CAR-T cells in adults.…”

“…Failure of blinatumomab was seen as a risk factor for CD19-negative relapse following CD19 CAR-T cells. 25 Recently a large cohort of patients reported long-term outcomes of children treated with different CAR-T-cell products, and suggested that CD28-based CAR-T cells were inferior to 4-1BB-costimulated products. 25 These data were based on two previously reported cohorts in which the LD regimens varied and in both one arm of conditioning was significantly inferior to the other.…”

Results of ARI‐0001 CART19 cell therapy in patients with relapsed/refractory CD19‐positive acute lymphoblastic leukemia with isolated extramedullary disease

“…Indeed, the graft versus leukemia effect conferred by alloHCT appears less effective for EMD compared to blood or bone marrow disease in some series, but not in others 17,18 . The results in small series of patients treated with CART19 cells are contradictory, but mostly revealing a worse outcome for patients with EMD 19–27 …”