Impact of Disease Burden, CAR-T Expansion, and Mononuclear Cell Recovery on Overall Response and Duration of Response in Zuma-3 Pivotal Study

Adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL) have an overall poor prognosis with standard-of-care therapies [1]. With the introduction of autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, Brexucabtagene autoleucel (brexu-cel), overall complete remission rates (OCR) have reached impressive levels of 71-73% [2,3]). Despite these strong positive outcomes with brexu-cel intervention in adult B-ALL, key questions remain unanswered which include i) ability to manufacture successful CAR-T products especially in the presence of high levels of circulating blasts/white blood cell counts, ii) impact of high pre-treatment disease burden in achieving durable response, iii) understanding brexu-cel expansion vs persistence as it relates to sustained remission, and iv) identifying patient population that would or would not benefit from consolidation with allogeneic stem cell transplant (allo-SCT).

Methods: We evaluated clinical and pharmacokinetic/pharmacodynamic data in context of best response and durability of response. Patient population consisted of 78 adults (≥ 18 years) with R/R B-ALL who received brexu-cel infusion in ZUMA-3 study Phase 1 and 2 at the pivotal dose (1×10⁶ CAR T cells/kg). Response rates were obtained via independent central review. Duration of response were classified into long duration (response lasting >12 months after achieving OCR), short/intermediate duration (response lasting <3/<12 months after achieving OCR), and non-responders. Patients that achieved OCR but proceeded to allo-SCT as consolidation of remission prior to 12-month evaluation were excluded.

Results: Approximately 18% of ZUMA-3 patients had elevated leukocyte or white blood cell (WBC) counts above upper limit of normal (11,000 cells per mL blood) at the time of leukapheresis. Despite the high number of circulating WBC, the apheresis material generated efficacious products that elicited robust rates of objective response. Among 78 patients that received the pivotal dose of brexu-cel, OCR was comparable between patients with high WBC vs those with normal WBC (71% vs 73% respectively). These data illustrate that high levels of circulating blasts or high WBC counts at the time of leukapheresis do not impact manufacturing of efficacious product. Furthermore, elevated WBC at leukapharesis had no impact in achieving durable responses. Currently, in the global Real World setting the manufacturing success rate of brexu-cel in adult B-ALL remains high at 97% in the last 12-month period (June 2023 to June 2024). Real World data demonstrate OCR at 79-91% which are comparable if not better than rates observed in ZUMA-3 [4,5].

Median bone marrow blast percent at baseline for patients in the pivotal cohort (n=78) was 63%. Notably, half of the patients who achieved long duration of response (>12 months) had a bone marrow blast percentage of 50% or higher. Additionally, CAR expansion within the first month post infusion [depicted as number of CAR-T cells in peripheral blood as well as area under the curve day_0-28] was significantly higher in patients who achieved long duration of response compared to non-responders. After 1 month post infusion, the number of persisting CAR-T cells in peripheral blood were low across patients. Combined, these findings indicate that expansion but not persistence of brexu-cel impacts overall response as well as durability of response. Persistence of CAR T-cells was not necessary for sustained remissions.

Lastly, analyses of endogenous immune cells day 28 post infusion showed numerically higher recovery of mononuclear cell (MNC) counts in patients that achieved long duration of response compared to non-responders (median - 820 vs 118 MNC /uL blood respectively). The levels were higher in both lymphocyte as well as monocyte counts at one month post infusion. These findings suggest that evaluation of mononuclear cell counts post infusion could be informative in understanding depth of response and perhaps in assessing if patients may or may not benefit from subsequent allo-SCT as consolidation of remission.

References

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2. Shah BD, et al. Lancet. 2021;398(10299):491-502
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