Impact of Current Manufacturing on Kymriah Real-World Effectiveness and Functional Persistence in Acute Lymphoblastic Leukemia (ALL) (KareALL): A Retrospective Study of Tisagenlecleucel (tisa-cel)-Treated Pediatric and Young Adult Patients (pts) with ALL
Authors: Rouce Rayne , Dolan J. Gregory , Phillips Christine L. , Qayed Muna , Pulsipher Michael A. , Vernau Lauren M. , Galletta Thomas J. , Votaw Sarah , Llaurador Caraballo Gabriela , Yang Hongbo , Wang Yao , Ghantoji Shashank , Tesfaye Mimi , Lee Soyon , O'Sullivan Emer , Grupp Stephan A. 
Published: December 2024

Introduction: Tisa-cel is a CD19-directed CAR-T cell therapy indicated for pts ≤25 y of age with B-ALL that is refractory or in ≥2nd relapse. Tisa-cel approval was based on the pivotal ELIANA trial, which demonstrated impressive efficacy and durability (ORR, 82%; 5 y RFS, 44%; 5 y EFS, 36%; and 5 y OS, 55%). Reports from CIBMTR show real-world use of tisa-cel continues to be safe and effective. ELIANA data suggest maintaining functional persistence (ie, B-cell aplasia) for ≥6 mo correlates with longer-term remission. To assess this finding with commercial tisa-cel, we compared outcomes from ELIANA with pts receiving tisa-cel manufactured using the most recent process.
Methods: KareALL is a retrospective, multicenter chart review study that collected real-world data through an electronic case report form to assess clinical outcomes among pts with r/r ALL. Pts had received commercial tisa-cel between December 2020 and ≥1 y before chart review. The primary endpoint was BOR. A key secondary endpoint was B-cell aplasia/recovery rate. Other secondary endpoints included MRD, DOR, RFS, EFS, OS, new anticancer therapy and/or alloSCT rate, IVIG use, and medical service use.
Results: As of January 26, 2024, data from 79 pts were collected from 5 treatment centers in the US. Median age was 13.5 y (range 0.5-25.6). Median follow-up (FU) was 18.7 mo (range 0.7-32.4). 57% of pts had primary refractory/chemorefractory disease; 28% received prior blinatumomab, 9% received prior inotuzumab, 9% received prior alloSCT. Most pts (92%) did not meet ELIANA inclusion/exclusion criteria. BOR (CR/CRi) rate at mo 1 was 78% (98% MRD negative) and was 90% (97% MRD negative) at mo 3. Significantly improved clinical response (P&lt;0.05) at mo 3 was observed in pts age &gt;3 y (vs 0-3 y), pts with no prior blinatumomab or inotuzumab exposure (vs prior exposure), and pts who received 1-2 prior therapies (vs &gt;2 prior therapies). Among the 71 responders, median DOR and RFS were not reached. Median EFS among all patients was 17 mo. In a multivariate analysis, predictors of significantly improved EFS (P&lt;0.05) included age &gt;3 y, only 1 prior therapy, no prior blinatumomab or inotuzumab exposure, and achieving B-cell aplasia. Median OS was not reached.
A total of 66 pts (84%) achieved B-cell aplasia. As of data cutoff 35 pts did not experience B-cell recovery. The estimated rate of maintenance of B-cell aplasia at mo 6 was 66%. 92% of pts (61/66) received Ig replacement therapy for B-cell aplasia. 56% of pts did not receive new cancer therapies after tisa-cel infusion. 43% of pts received an alloSCT after tisa-cel infusion, 12% of which were pre-planned at time of infusion. 65% of pts who went on to alloSCT (22/34) were in B-cell recovery at time of transplant; 71% of pts (24/34) were relapse free prior to alloSCT.
The majority of pts (63%) were not hospitalized at time of tisa-cel infusion. Pts with low disease burden (&lt;5% lymphoblasts in BM), Karnofsky or Lansky PS of 100, and without disease relapse within 18 mo of diagnosis were significantly more likely to be infused in the outpatient setting (P&lt;0.05). 32/50 pts infused in the outpatient setting required subsequent hospitalization. After infusion, 66% of pts experienced CRS, and 14% of pts experienced a serious infection. Median time to recovery was 29 d for neutropenia, 46 d for anemia, and 61 d for thrombocytopenia. CRS lasted median 5 d (range 1-20). A greater proportion of patients who were infused as inpatients were admitted to ICU after tisa-cel infusion (41% vs 18%; P&lt;0.05).
Conclusions: Commercial tisa-cel use in the US continues to demonstrate compelling clinical benefits, with high remission rates and sustained response. More than half of pts safely received outpatient tisa-cel infusion, reducing medical service use, without compromising efficacy. Despite the curative potential discussed in previous reports, 71% of pts received alloSCT while in remission. B-cell recovery is increasingly being used to guide decisions for alloSCT; knowing that current manufacturing maintains an estimated functional persistence rate of 66% at 6 mo may help in making subsequent treatment decisions. Furthermore, NGS MRD may also be helpful in assessing risk of relapse and need for additional therapies, including HSCT. Studies exploring consolidative HSCT in pts who are in remission after CAR-T are needed to evaluate whether HSCT further improves pt outcomes.