Impact of disease burden and loss of BCA on outcomes after tisa-cel infusion in pediatric and young adults with R/R B-ALL

High disease burden has been associated with risk for relapse in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). Loss of B-cell aplasia (BCA) is a biomarker of functional loss of CD19 CAR T-cells; however, its impact on outcomes and the optimal management of these patients remains unclear.¹

Here, we summarize a multicenter retrospective study published by Molinos-Quintana et al. in Frontiers in Immunology, assessing the impact of pre-infusion tumor burden and loss of BCA in patients with R/R B-ALL treated with tisagenlecleucel (tisa-cel).

Study design¹

• This study included 73 children and young adults with R/R B-ALL who were given a single infusion of tisa-cel across five different Spanish institutions.
• BCA was monitored by multicolor flow cytometry:
  • Loss of BCA was defined as the presence of >1% of B lymphocytes in peripheral blood lymphocytes or >3% of total white blood cells or ≥1% of CD19-positive B-cell population in bone marrow.
  • Ongoing BCA was defined as persistent BCA in the absence of CD19-positive relapse at any site.

Key findings¹

• At Day 28 post-infusion:
  • Complete remission/complete remission with incomplete hematologic recovery and minimal residual disease-negativity was achieved by 90.4% of patients
  • Death due to severe cytokine release syndrome was reported in 2.7% of patients
  • At a median follow-up of 13.5 months, 59% of patients experienced relapse, of which 56.4% had CD19-negative disease
• Overall, 41% of patients maintained complete remission, while 44.4% had ongoing BCA, and 54% displayed loss of BCA with CD-19 positive relapse.

Outcomes based on pre-infusion tumor burden

• CD19-negative relapses occurred in 72% of patients in the high tumor burden (HTB) group, whereas relapses in the low tumour burden (LTB) group were mainly CD19-positive and occurred in 71% of patients (p = 0.017).
• The median time to CD19-negative relapse was 3 and 6.5 months, while the median time to CD19-positive relapse was 10 and 13 months in the HTB vs LTB group, respectively.
• The median EFS was not reach in the LTB group vs 5 months in the HTB group; the 12-month EFS was significantly higher in the LTB vs HTB (p < 0.001) group (Figure 1).

EFS, event-free survival; HTB, high tumor burden; LTB, low tumor burden.
*Data from Molinos-Quintana, et al.^1
†>5% of BM blasts.
^‡<5% BM blasts. 

Outcomes based on BCA maintenance and timing

• Loss of BCA was reported in 19.2% and 80.8% of patients in HTB and LTB group, respectively.
• The median time to loss of BCA post-infusion was 6 and 11 months in LTB vs HTB group, respectively.
• CD19-positive relapses occurred after the loss of BCA in 100% vs 57% in LTB and HTB group, respectively.
  • There was a positive correlation between loss of BCA and CD19-positive relapses
• A total of 57.1% patients with LTB lost BCA within the first 6 months; 41.6% of these patients underwent allogenic hematopoietic stem cell transplantation (allo-HSCT) and 8.3% relapsed.
• Of the 75% patients who lost BCA ≥6 months post-infusion, 67% subsequently had CD19-positive relapse.

Key learnings

High tumor burden had a negative impact on EFS; therefore, allo-HSCT should be considered in these patients, irrespective of B-cell aplasia. Allo-HSCT can also be considered in patients with low tumor burden with loss of B-cell aplasia <3–6 months after treatment. For patients with low tumor burden and loss of B-cell aplasia >6 months after treatment, close MRD monitoring and/or personalized treatment approaches should be considered.