Tisagenlecleucel Maintains Durable Response at 5 Years in Pediatric/Young Adult Patients With B-ALL

Long-term follow-up from the phase 2 ELIANA trial (NCT02435849), showed that tisagenlecleucel (Kymriah) continued to demonstrate durable efficacy in heavily pretreated pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). The final analysis of the findings was presented at the 2022 EHA Congress.¹

Among 79 patients, with a median age of 11 years (range, 3-24), the overall remission rate (ORR) was 82% with a complete remission (CR) rate of 62% and a CR with incomplete blood count recovery (CRi) rate was 20%. Additionally, 98% of patients who achieved remission had minimal residual disease (MRD) negativity at 3 months.

Among 65 responders, the median relapse-free survival (RFS) was 43 months (95% CI, 12- not estimable [NE]). The 5-year RFS rate was 44% (95% CI, 31%-56%).

“Long term remission rates up to 5.9 years of follow up from ELIANA demonstrate that tisagenlecleucel may be a curative treatment option for heavily pretreated pediatric and young adult patients with relapsed or refractory B-ALL,” Susana Rives, MD, PhD, said in a presentation of the data. Rives is a specialist physician in the Pediatric Oncology Department of Sant Joan de Déu Barcelona Children’s Hospital and head of the Hematopoietic System Tumors Unit at the Sant Joan de Déu Hospital, in Spain.

ELIANA enrolled patients with relapsed or refractory B-cell ALL between the ages of 3 and 21 years with bone marrow lymphobasts of at least 5% who had not received prior CD19-directed therapy. Patients received lymphodepleting chemotherapy prior to infusion comprising 30 mg/m2 of intravenous (IV) fludarabine daily for 4 doses with cyclophosphamide 500 mg/m2 IV daily for 2 doses.

Patients proceeded to a single infusion of tisagenlecleucel based on weight at the time of infusion. For patients weighing over 50 kg, the dose range was 0.1 to 2.5 × 108 cells and for those weighing 50 kg or less the dose range was 0.2 to 5.0 × 106 cells. The primary end point was ORR within 3 months, and 4-week maintenance of remission by independent review committee assessment. Secondary end points included MRD status, duration of response, RFS, event-free survival (EFS), overall survival (OS), cellular kinetics, and safety.

At baseline, the median number of prior lines of therapy was 3 (range, 1-8) and 61% of patients has prior allogeneic stem cell transplantation (alloSCT). Most patients had primary refractory disease status (92%) and the median morphologic blast count in bone marrow was 74% (range, 5%-99%).

At the time of last evaluation, 31 patients were in remission with a median follow-up of 60.1 months (range, 25.3-68.5).

The median EFS was 15 months (95% CI, 10-45) with a 5-year EFS rate of 36% (95% CI, 25%-47%). When censoring for patients who underwent alloSCT the median EFS was 13 months (95% CI, 9-35) with a 5-year EFS rate of 34% (95% CI, 23%-45%).

Further, at the time of the final analysis the median OS was not reached (95% CI, 46- NE). At 5 years, 55% of patients were alive (95% CI, 43%-66%).

Investigators reported that the probability of B-cell aplasia was 83% (95% CI, 71%-91%) at 6 months and 71% (95% CI, 57%-82%) at 12 months. The median time to B-cell recovery was 39 months and among those who achieved B-cell recovery the cumulative incidence of relapse was 40%.

Following infusion with tisagenlecleucel, 25% of patients underwent alloSCT. Investigators noted that 4 patients had alloSCT within 3 months of receiving the CD19-directed CAR T-cell therapy. In total, 10 patients underwent transplant in remission and 7 had alloSCT and the remaining 14 underwent transplant after 3 months.

Investigators noted that results for OS and EFS between pediatric (< 18 years) vs young adult patients (≥ 18 years) were comparable. Among 65 pediatric patients the median OS was not reached (95% CI, 44-NE) vs 57 months (95% CI, 10-NE) among 14 young adult patients. The median EFS was 15 months for both populations.

Rives noted that no new long-term treatment-related safety events were reported in the long-term analysis. Adverse effects of special interest (AESIs) observed after 1 year post infusion were reported at the meeting.

Among patients who achieved remission at any time during the study, including those who received a response at any time (n = 70), 39% had at least 1 AESI of any grade and 21% had an AESI grade 3 or higher.

The most commonly reported AESI was infection with any-grade incidence of 33% and grade 3 or higher incidence reported among 20% of patients. All-grade hemaphagocytic lymphohistiocytosis or cytokine release syndrome was reported in 1 patient and was grade 3 or higher. Serious neurologic events occurred in 3% of patients with 1 event grade 3 or higher. Hematological disorders, including cytopenias, were reported in 10% of patients, and 4 events were grade 3 or higher.

“We had a patient with a secondary malignancy—a myelodysplasia—this patient had a prior [allogeneic] transplant with [total body irradiation] TBI and with and high cumulative doses of etoposide, cyclophosphamide, and tricyclines, but still she had moderate cytopenias with severe dysplastic signs in peripheral blood and bone marrow,” Rives said adding that the patient received no further therapy and the cytopenias are stable.

A majority of patients (82%) received immunoglobulin IV at any time post infusion with 33% of patients receiving the infusion after 1 year and 16% after 2 years. Further, 88% of patients in remission received immunoglobulin IV during persistent B-cell aplasia.

Tisagenlecleucel was approved for use in pediatric and young adult patients with B-ALL in 2017 based on earlier data from the ELIANA study.2 In data that led to the approval, the ORR was 83% (95% CI, 71%-91%) among 63 evaluable patients and the median duration of remission was not reached. MRD negativity was reported in all responders.²

References

1. Rives S, Maude AL, Hiramatsu H, et al. Tisagenlecleucel in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia: final analyses from the ELIANA study. Presented at: 2022 EHA Congress. June 9-17, 2022; Vienna, Austria. Abstract S112.
2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed June 13, 2022. bit.ly/3aWMs6o