S1618 Tisagenlecleucel Appears Effective and Safe in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia With High‐risk Cytogenetic Abnormalities

Abstract

Although most patients (pts) achieve complete remission (CR) following intensive chemotherapy, relapse occurs in about 50% of the cases and is associated with poor prognosis. In this AML subset monitoring of measurable residual disease (MRD) has been shown to identify pts at higher risk of relapse. Aims: To assess the prognostic impact of MRD monitoring in bone marrow (BM) and peripheral blood (PB) in a large cohort of 155 homogeneously treated and clinically well-annotated patients with t(8;21)-AML. Methods: Quantification of RUNX1-RUNX1T1 transcript levels (TL) was performed by RT-qPCR. TL were reported as normalized values of RUNX1-RUNX1T1 per 10 6 transcripts of the housekeeping gene B2 M. Samples were analyzed in triplicate, the sensitivity of our assay was up to 10 -6 . Results: While pretreatment RUNX1-RUNX1T1 TL did not impact prognosis, both reduction of RUNX1-RUNX1T1 TL and achievement of MRD negativity (MRD neg ) at defined time points were of significant prognostic importance. First, achievement of MR 2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR 3.0 after cycle 2 were significantly associated with a reduced risk of relapse (P = 0.034 and P = 0.028, respectively). Second, after completion of therapy, achievement of MRD neg in both, BM and PB, was an independent favorable prognostic factor for cumulative incidence of relapse (4-year CIR BM: 17% vs 36%, P = 0.021; PB: 23% vs 55%; P = 0.001) and overall survival (4-year OS rate BM: 93% vs 70%, P = 0.007; PB: 87% vs 47%; P < 0.0001). Finally, during follow-up serial RT-qPCR analyses allowed prediction of relapse in 77% of pts exceeding a cut-off of 150 RUNX1-RUNX1T1 TL in BM, and in 84% of pts with > 50 RUNX1-RUNX1T1 TL in PB, respectively. KIT mutation observed in 28% of pts predicted for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TL during treatment. Virtually all relapses occurred within one year after end of treatment (EOT) with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this period. Based on our data we suggest a refined practical guideline for MRD assessment in RUNX1-RUNX1T1-positive AML: Along with the current ELN MRD recommendations, BM and PB should be analyzed after each treatment cycle. According to MRD at EOT and during follow-up we suggest MRD monitoring as follows: (i) MRD neg : PB monthly can be used, (ii) MRD pos (TL < 150 in BM and < 50 in PB): BM 3-monthly and PB monthly, and (iii) MRD pos (TL >150 in BM and/or >50 in PB) or increase of MRD >1-log or conversion from MRD neg to MRD pos : BM and PB, both monthly, should be analyzed. Summary/Conclusion: RUNX1-RUNX1T1 MRD monitoring allows for the discrimination of pts at high and low risk of relapse. MRD neg in both, BM and PB, after completion of therapy was the most valuable independent favorable prognostic factor for relapse risk and OS. During follow-up, serial MRD analyses allowed the definition of cut-offs predicting relapse. Moreover, con...

Highlights of the 24th European Hematology Association Congress, Amsterdam 2019

“…Close attention is currently paid to the study of CAR-T therapy effects in the patients with refractory ALL. According to a retrospective analysis of ELIANA and ENSIGN studies by Grupp S. et al, Tisagenlecleucel appeared effective, with high rates of durable responses, prolonged survival, and a manageable safety profile in patients with high-risk cytogenetic abnormalities with historically poor prognosis (median OS was not reached, 12-year and 24-year survival probability was 74.9% and 66.6%, respectively vs 70.7% and 58.8% in patients without high-risk cytogenetic abnormalities) [26].…”