Chemotherapy or Stem Cell Transplantation in Adult High Risk Ph/BCR::ABL1-Negative ALL Patients with Early MRD Negativity: Results of the Randomized GMALL Trial 08/2013

Outcome of adult ALL was improved significantly using pediatric (ped) -based therapy over the past decade. However, many groups still see an indication for stem cell transplantation (SCT) in patients (pts) with high-risk (HR) features. The GMALL Trial 08/2013 (NCT02881086) for pts aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a ped-based regimen with MRD-based stratification and risk adapted SCT (Gökbuget et al, ASH 2021). Induction has 2 phases (IP1/IP2) and is followed by intensive consolidation I (C1). Indication for SCT is based on features detected at diagnosis (B-precursor: WBC >30,000/μl, proB subtype, KMT2a-rearrangement; T-lineage: early/mature subtype), no achievement of hematologic CR after IP1 or molecular failure after C1. SCT was scheduled after C1. Standard risk (SR) therapy consists of cycles with HDMTX/PEG-ASP, HDAC/CYCLO, reinduction and maintenance with MP/MTX up to a total treatment duration of 2.5 yrs.

The trial included a randomization for Ph negative HR ALL pts with available donor and molecular CR (molCR i.e. negative MRD with a sensitivity of 0.01% by quantitative PCR of IG/TR in GMALL reference lab) after IP2. Pts were either scheduled for SCT (matched related/unrelated) or SR chemotherapy with MRD follow-up. The statistical assumption (primary endpoint) was to detect in 88 pts with a power >90% and a 2-sided α-level of 5% an improvement of disease-free survival (DFS) from 70% to 86% at 3.5 yrs. Events were hematologic relapse (hemR), molecular relapse (molR), secondary malignancy or death in CR (TRM). HemR was defined by conventional criteria. MolR was defined as MRD >=0.01% after prior molCR. Probabilities of TRM and hemR were calculated with competing risks.

Between 8/16-8/22 1023 pts from 78 centers were included in the trial. 285 pts had HR ALL. 102 pts (37%) achieved molCR after IP2; 96 pts were randomized (91%). Pt characteristics were evenly distributed between both arms; median age was 31 (18-55) yrs and 63% had B- (36% c/preB; 26% pro B) and vs 38% T-subtype (19% early; 14% mature; 5% thymic) respectively (resp).

Scheduled therapy was performed in 79% (38/48) for SCT arm and 88% (42/48) for SR arm resp. Deviations resulted from pt wish (N=7; of this N=6 in SCT arm), randomization despite exclusion criteria (N=3 e.g. pt with SR ALL) and unavailable donor/other (N=2/1).Three pts were not eligible for evaluation of treatment realization since they dropped out (2 pt wish, 1 wrong diagnosis); they were included in the outcome analysis. All analyses were performed in the intent-to-treat population.

3y DFS was identical in both arms (SCT arm 76% [61, 86]; SR arm 71% [55, 82]) (p>.05). Six (13%) vs 4 (8%) pts died in CR in SCT vs SR arm resp. (3yTRM: 13% [5; 24] vs 9% [3; 19]). 5 (10%)/ 7(15%) had hemR in SCT vs SR arm resp (3y RR: 11% [4; 22] vs 15% [7; 27]). 9/12 hemR were preceded by molR whereas 3 pts had hemR w/o prior molR. 9/11 pts with molR progressed to hemR and 9/11 died whereas 3/3 pts with direct hemR died.

3y OS was 76% vs 75%C in SCT vs SR arm resp (p>.05). Post-hoc analyses of subtypes revealed differences. In B-lineage the 3y DFS for SCT (N=31) vs SR (N=29) arm was 81% vs 56% resp (p=0.04). 3y OS was 80% vs 60% resp (p>.05). One pt relapsed in the SCT arm (not transplanted per pt wish) vs 8 pt with hem/molR (1 molR) in SR arm. 2/8 relapse cases had BCR::ABL-like (JAK/STAT) an 2/8 KMT2Ar ALL. In T-ALL DFS for SCT (N=17) vs SR arm (N=19) was 67% vs 94% (p=0.04). 3y OS was 69% vs 100% resp. 4 pts relapsed in SCT arm vs 1 (including 1 molR) in SR arm. Further analyses of long-term effects and quality of life is ongoing.

The GMALL trial 08 demonstrated a successful randomization of SCT in a complex multicentre setting. The primary endpoint was not reached. Overall results were similar comparing SCT vs SR therapy in HR pts with early molCR. While SCT pts had a higher TRM, SR therapy was associated with more relapses. In B-precursor ALL the trend was in favor of SCT in contrast to T-ALL with better outcomes in the SR arm. Whereas upcoming relapse was often identified by MRD testing, salvage after molR or hemR was rarely successful and outcome was extremely poor. This indicates the role of careful upfront definition of SCT indications. In further GMALL trials the upfront use of Blinatumomab for further improvement of B-precursor ALL with MolCR will be evaluated whereas SCT indication may be maintained in selected HR pts despite molCR. GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe (111440).