Correlation of Minimal Residual Disease (MRD) at the End of Induction (EOI) and Event Free Survival (EFS) in T-Cell Lymphoblastic Lymphoma (T-LL), a Report from the Children's Oncology Group (COG) Trial AALL1231

Background: Defining prognostic variables that correlate to EFS in T-LL remains a clinical challenge. Traditional variables such as stage or radiologic response to therapy have failed to correlate with EFS in recent trials. AALL1231 was a COG phase 3 clinical trial for newly diagnosed with T Acute Lymphoblastic leukemia (T-ALL) or T-LL patients that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone with no bortezomib (Arm A) or with bortezomib (Arm B) during induction and delayed intensification (DI) (1.3mg/m² x 4 doses per block). T-LL patients were stratified as standard (SR), intermediate (IR), or very high risk (VHR), based upon minimal detectable disease (MDD) in the bone marrow at diagnosis, prior steroid pre-treatment and radiographic response at the end of induction. Bone marrow (BM) samples to assess MRD by flow cytometry at the EOI were an optional submission for T-LL participants and those collected were analyzed to assess its correlation to EFS.

Results: AALL1231 accrued 209 T-LL patients from 2014 until closure in 2017. At the end of induction, 43.6% were in radiologic remission, 55.4% had a partial response and 1% had stable disease or no response. There were 86 (41%) patients for whom EOI samples for MRD assessment were submitted. Patients with MRD <0.1% (n=75) at EOI had a superior EFS versus those with MRD >0.1% (n= 11), (89.0 + 4.4% verses 63.6 + 17.2%, p= 0.025). Overall survival did not significantly differ between the two groups (88.9 + 4.4% versus 72.7 + 15.5% p= 0.15). As previously reported, Arm B demonstrated a superior outcome for both EFS and OS for the entire cohort. Within risk groups, IR and SR patients had similar EFS outcomes (Arm A 73.9 + 7.5% versus 80.4 + 6.7, Arm B 87.2 + 5.8 % versus 90.5 + 4.8%) with only two patients the VHR, both in Arm B. Cox regression for EFS using Arm A as a reference demonstrated that MRD EOI ≥0.1% was associated with a greater risk of inferior outcome (Hazard Ratio, HR = 3.73 (1.12-12.40, p = 0.032), (Table 1) which was independent of treatment arm assignment. OS failed to reach statistical significance for patients MRD EOI ≥0.1%, HR = 2.714 (0.72-10.44, p=0.14). Furthermore, Cox regression failed to demonstrate a superior EFS with decreasing MDD at diagnosis (>5% versus 1-5%, versus <1%), HR=2.67 (0.336-21.145, p=0.141, HR= 0.830 (0.255-2.699, HR= 0.57 (0.289-1.073, p= 0.080)(Table 2).

Conclusions: In this pediatric T-LL trial, BM EOI MRD by flow cytometry was associated with improved EFS in in both arms (+/- bortezomib) in both univariate and multivariate analyses. In contrast, race, age, gender, risk group, MDD, stage and radiologic response to therapy were not prognostic. Consideration to incorporate MRD at EOI into the design of future trials will establish its value in defining risk groups for subsequent therapeutic trials.

Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Teachey:BEAM Therapeutics: Consultancy; Sobi: Consultancy. August:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees. Freedman:Massive Bio, Inc: Consultancy, Current holder of stock options in a privately-held company. Shimano:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Principia Biopharma: Research Funding; Dova Pharmaceuticals: Research Funding. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Hunger:Servier: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Amgen: Current equity holder in private company. Raetz:Pfizer: Research Funding; BMS: Other: Data and Safety Monitoring Board. Bollard:Mana Therapeutics: Current equity holder in private company, Current holder of stock options in a privately-held company, Other: scientific ci-founder and SAB member, Patents & Royalties: VSTs/TAA-T; Neximmune: Current equity holder in private company; BMS: Consultancy; SOBI: Other: DSMB member; Catamaran Bio: Current equity holder in private company, Current holder of stock options in a privately-held company, Other: scientific ci-founder and SAB member; Repertoire Immune Medicines: Current equity holder in private company; Cabalatte Bio: Membership on an entity's Board of Directors or advisory committees; Cellmedica: Patents & Royalties; Roche: Consultancy; Pfizer: Consultancy.