Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia

BACKGROUND

Tisagenlecleucel is an FDA approved chimeric antigen receptor (CAR)-T cell therapy that reprograms T cells to eliminate CD19+ B cells. ELIANA (NCT02435849) is a phase 2 pivotal study of tisagenlecleucel in pediatric/young adult patients (pts) with CD19+ r/r B-cell acute lymphoblastic leukemia (ALL), the first global trial of a CAR-T cell therapy. The primary objective was met, with an overall remission rate (ORR) of 81% (complete remission [CR] + CR with incomplete blood count recovery [CRi]). Here we present an update of ELIANA, with additional pts and additional 11 mo follow-up from the previous report (Maude et al. N Engl J Med 2018).

METHODS

Eligible pts were aged ≥3 y at screening and ≤21 y at diagnosis and had ≥5% leukemic blasts in bone marrow. Tisagenlecleucel was centrally manufactured at 2 sites (Morris Plains, NJ, USA and Leipzig, Germany) by lentiviral transduction of autologous T cells with a vector encoding for a second generation 4-1BB anti-CD19 CAR and expanded ex vivo. Tisagenlecleucel was provided to pts at 25 study centers in 11 countries on 4 continents using cryopreserved apheresed mononuclear cells, central production facilities, and a global supply chain. The primary endpoint, ORR within 3 mo and maintained for ≥28 d among infused pts, was assessed by an independent review committee. Secondary endpoints included duration of remission (DOR), overall survival (OS), safety, and cellular kinetics.

RESULTS

As of April 13, 2018, 113 pts were screened and 97 enrolled. There were 8 manufacturing failures (8%) and 10 pts (10%) were not infused due to death or adverse events (AEs). Following lymphodepleting chemotherapy in most pts (76/79; fludarabine/cyclophosphamide [n=75]), 79 pts were infused with a single dose of tisagenlecleucel (median dose, 3.0×10⁶ [range, 0.2-5.4×10⁶] CAR-positive viable T cells/kg), and all had ≥3 mo of follow-up or discontinued earlier (median time from infusion to data cutoff, 24 mo [range, 4.5-35 mo]). Median age was 11 y (range, 3-24 y); 61% of pts had prior hematopoietic stem cell transplant (SCT).

Among the 65 pts with CR/CRi, 64 (98%) were MRD- within 3 mo. Median DOR by K-M analysis was not reached (Figure): responses were ongoing in 29 pts (max DOR, 29 mo and ongoing); 19 pts relapsed before receiving additional anticancer therapy (13 died subsequently); 8 pts underwent SCT while in remission, 8 received additional anticancer therapy (non-SCT) and 1 discontinued while in remission. The probability of relapse-free survival at 18 mo was 66% (95% CI, 52%-77%). Median OS was not reached; OS probability at 18 mo was 70% (95% CI, 58%-79%).

Cytokine release syndrome (CRS) occurred in 77% of pts (grade [G] 3/4; 48%; graded using the Penn scale); 39% of pts received tocilizumab for treatment of CRS with or without other anti-cytokine therapies; 48% of pts required ICU-level care for CRS, with a median ICU stay of 7 d. All cases of CRS were reversible. Most common G 3/4 nonhematologic AEs (>15%) other than CRS were neutropenia with a body temperature >38.3°C (62% within 8 wk of infusion), hypoxia (20%), and hypotension (20%). 13% of pts experienced G 3 neurological events, with no G 4 events or cerebral edema. Based on laboratory results, 43% and 54% of pts had G 3/4 thrombocytopenia and neutropenia not resolved by d 28; the majority of events resolved to G ≤2 by 3 mo. 25 post-infusion deaths were reported: 2 within 30 d (1 disease progression, 1 cerebral hemorrhage); 23 after 30 d of infusion (range, 53-859 d; 18 disease progression, 1 each due to encephalitis, systemic mycosis, VOD [hepatobiliary disorders related to allogeneic-SCT], bacterial lung infection, and an unknown reason after study withdrawal).

Tisagenlecleucel expansion in vivo correlated with CRS severity, and persistence of tisagenlecleucel along with B-cell aplasia in peripheral blood was observed for ≥2.5 y in some responding pts. Analysis of B-cell recovery and correlation with relapse will be presented.

CONCLUSIONS

With longer follow-up, the ELIANA study continues to confirm the efficacy of a single infusion of tisagenlecleucel in pediatric and young adults with ALL without additional therapy. AEs were effectively and reproducibly managed globally by appropriately trained personnel at study sites. The achievement of high overall response rates and deep remissions, in combination with the median duration of response and overall survival not being reached, further corroborate previously reported results.

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