CD19-CAR-T Cells Are Effective and Safe Treatment of Post-Transplant Relapse in Pediatric and Young Adult Patients with B-Lineage ALL: Real-World Data from Germany

Introduction: Patients with precursor-B acute lymphoblastic leukemia (pre-B ALL) which have relapsed subsequent to allogeneic hematopoietic stem cell transplantation (HSCT), have relapsed twice, or were resistant to upfront therapy have a dismal prognosis. CD19-directed chimeric antigen receptor (CAR) T cells have evolved as potent immune therapy for such patients. Tisagenlecleucel (Tisa-cel) is a commercial CD19-directed autologous CAR-T cell product. The CAR contains the co-stimulatory element 4-1BB to promote in vivo persistence and proliferation. Thus this therapy is in principle competent to serve as a stand-alone therapy. Based on the results of the ELIANA trial (Maude et al. NEJM 2017), Tisa-cel was approved by FDA and EMA for pediatric/young adult B-ALL in 2017 and 2018. In clinical trials, stringent inclusion criteria narrow down the risk profiles of trial subjects. Treatment in clinical trials provides close guidance to physicians and patients during the trial. However, post approval reality leads to treatment of patients with higher and more variable risk profiles treated in many centers. With approval by the local ethics committees, we performed a retrospective study asking all CAR T cell centers in Germany approved for treatment with Tisa-cel (Kymriah®) to provide treatment data reflecting post approval reality, in order to identify patients who might most benefit from this novel, complex and expensive treatment.

Patients: Twenty-one centers included all pediatric and young adult patients with pre-B ALL (n=81) who had received Tisa-cel between 8/2018-1/2022, allowing for a minimal follow-up of 5 months of surviving patients. Median age was 11.5 years (range: 1.0-25.0 years), 53 (65.4%) were male and 28 (34.6%) female, median body weight was 41.6 kg (range: 8.0 kg-135 kg). 65 patients (80.2%) had relapsed after HSCT, 15 (18.5%) had suffered a 2^nd relapse without HSCT and 1 had primary refractory disease. For bridging therapy, 3 patients (3.7%) received Blinatumomab, 4 (4.9%) inotuzumab, 72 (88.9%) received low-dose chemotherapy. One patient was bridged with a high-dose chemotherapy; 1 patient with extra-medullary disease did not receive any bridging therapy.

Results: Cytokine release syndrome (CRS) was observed in 55 (67.9%) patients (grade I-II: n=50, Grade III-IV: n=4 and grade V: n=1); immune cell-associated neurological syndrome (ICANS) was seen in 6 (7.4%) patients (grade I: n=2, grade III-IV: n=4). At day 28, 72 patients (88.9%) were in CR, 8 (9.9%) in NR. One patient (1.2%) succumbed to CRS. At last follow-up, 42 patients (60%) remained in remission, 34 patients had relapsed, 1 died of TRM, 3 of NRM, 1 had developed secondary MDS. This translated into an event-free survival probability (pEFS) of 43.9% (±6.5), an of overall survival (pOS) of 52.9% (±7.0), and a cumulative incidence of relapse (CIR) of 48.8% (±6.4) at 2 years post CAR T cell transfusion. CIR CD19 neg. was 33.8% (±6.1%) and CIR CD19 pos. was 15% (±4.2%). Interestingly, there was no difference between children and adult patients with regard to pEFS and pOS.

A trend towards a higher pEFS (n=16, 55.0±12.7%) compared to patients receiving CAR-T for relapse after alloHSCT (n=65, 41.8±7.2%) was observed (p=0.630). Time to relapse after HSCT was a strong predictor for outcome. Patients relapsing within 6 months of HSCT had a pEFS (pOS) of 17.2±9.6% (15.6±9.6%), pEFS (pOS) for those relapsing later was 53.8±9.0% (74.5±8.0%) p=0.001), Figure 1.

Risk factors: For the subgroup with post HSCT relapse, multivariable Cox-regression analysis considering age, time from HSCT to relapse, extra-medullary relapse, remission status at start of lymphodepleting chemotherapy (LDC) and LDC dosing revealed that time from HSCT to relapse >6 months’ post HSCT as a single factor reduced the risk to 0.381 and 0.221, respectively (p=0.001 and p=0.003), Table 1.

Conclusion: In our analysis providing the first real-world experience in a patient cohort highly enriched for patients with post HSCT relapse, 40% of ALL patients with poor prognosis were rescued with a single dose of Tisa-cel. Our novel finding that patients post HSCT had a far better EFS if relapse occurred beyond 6 months might be attributable to more competent T-cell system with more native T-cells with higher plasticity for proliferation, expansion and persistence. This is currently a matter of investigation and may in future allow to implement strategies to optimize CAR T cell therapies.

Bader:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Research Funding; Neovii: Research Funding; Riemser: Research Funding, Speakers Bureau; Medac: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Miltenyi: Speakers Bureau. Rossig:Pfizer: Honoraria; Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; MSD: Honoraria. Ayuk:Mallinckrodt/Therakos: Honoraria, Research Funding; Medac: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene/BMS: Honoraria; Miltenyi Biomedicine: Honoraria. Buecklein:Amgen: Honoraria; Pfizer: Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Miltenyi Biotech: Research Funding; Gilead: Honoraria. Einsele:BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Other: travel grants. Holtick:Novartis: Honoraria, Research Funding; Miltenyi Biotech: Honoraria; BMS/Celgene: Honoraria; Amgen: Consultancy, Honoraria; CLS Behring: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Kite/Gilead: Honoraria. Koenecke:Novartis: Membership on an entity's Board of Directors or advisory committees. Künkele:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Meisel:Jazz: Research Funding; MEDAC: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Gilead/KITE: Research Funding; Neovii: Research Funding; Bellicum: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRISPR Therapeutics/Vertex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Penack:Gilead: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees; Priothera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; SOBI: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Equillium Bio: Membership on an entity's Board of Directors or advisory committees; Therakos: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. von Stackelberg:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Speakers Bureau; Clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jarisch:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.