Abstract
The German Multicenter Study Group for Adult ALL (GMALL) has maintained a prospective national registry (NCT02872987) since 2009, enrolling newly diagnosed adult ALL patients (pts) treated under standard protocols in 150 hospitals. Epidemiologic coverage is ~90% for age 18–55 years (yrs), yielding near population-based data. Therapy is pediatric-inspired, age-adapted chemotherapy with risk-adapted stem cell transplantation (SCT).
Based on the ECOG1910 trial (Litzow et al., N Engl J Med, 2024), the GMALL modified standard therapy for Ph-neg B-precursor ALL in 8/23 by integrating 3 cycles of Blinatumomab (Blina) intermittently with chemotherapy. The revised schedule: Ind I/II – Cons I – Blina I (SCT in younger HR pts) – Cons II – Reind – Blina II – Cons III – Cons IV – Cons V (not in older pts) – Blina III – Maintenance up to 2.5 yrs. Chemotherapy differed between ‘younger’ (18–55 yrs) and ‘older’ (56–75 yrs) pts.
We compared outcomes of pts (18–75 yrs) treated with the modified protocol (cohort 1, 8/23–8/24) to those receiving Blina only for persistent/recurrent minimal residual disease (MRD) in cohort 2 (8/16-8/23). The latter included pts aged 18-55 yrs from trial GMALL 08 or standard protocols for pts aged 18-75 yrs not treated in the trial. MRD was assessed centrally via IG/TR rearrangements. Responses were defined as molecular CR (MolCR, MRD neg with sensitivity <10⁻⁴), molecular failure (MolFail, MRD ≥10⁻⁴), or intermediate (IMR, low-pos/non-quantifiable). Median follow-up was 14 (0.2–22) vs. 46 (0.3–104) months (mo) for cohorts 1 and 2, respectively (resp).
Cohorts 1 and 2 included 199 (131 young/68 old) and 1036 pts (737/299) resp. In cohort 2, 62% of younger pts were treated in GMALL 08; 40% had HR subtypes. CR after ind was 95% vs 79% (young vs old); early death rates were 3% vs 13%. After Cons I, MolCR/IMR/MolFail rates were 73%/15%/13% (young) and 43%/29%/29% (older). Cohort 2 showed no significant differences in terms of pt characteristics and MRD response compared to cohort 1.
Among CR pts in cohort 1, 76% vs 65% received Blina I (young vs old); main reasons for omission were organizational; only 3 pts declined Blina. The proportion of pts treated in MolFail vs MolCR vs IMR were 10% / 69% / 17% in the young and 26% / 29% / 37% in the old group highlighting the different patterns for use of Blina in both age groups. Overall Survival (OS) at 18 mo was 91% (young) and 74% (old). Death in CR occurred in 2% and 1%, resp. Further comparisons refer to OS at 18 mo; p-values are given if <0.05.
OS was 91% vs 83% (cohort 1 vs 2) in young pts and 74% vs 64% in old pts. Among pts with CR post-induction, OS was 95% vs 90% (young) and 87% vs 77% (old). OS by MRD response (cohort 1 vs 2) in young pts was: MolFail 92% vs 85%, IMR 94% vs 79%, MolCR 96% vs 92%; in old: MolFail 80% vs 62%, IMR 94% vs 73%, MolCR 93% vs 88%. In old pts aged 65–75 yrs, OS was 73% vs 56% (cohort 1 vs 2). In young HR pts, OS was 87% vs 75%; in standard-risk pts, 95% vs 90%. In young pts, OS was highest in cohort 1 (85%) and GMALL 08 (89%), and lowest in cohort 2 non-trial pts (75%) (p<0.0001).
These intent-to-treat data suggest that integrating Blina prospectively into standard, age-adapted protocols can contribute to favorable early outcomes across age, risk, and MRD subgroups in standard of care. While not statistically significant, benefits were more evident in IMR and HR pts. Updated data with longer follow-up will be presented. Notably, logistical issues led to omission of Blina I in a significant number of pts (even more in older pts), underscoring the advantages of clinical trials over routine care. Consequently, outcomes were more favorable in younger pts treated within the GMALL 08 trial compared to historic standard of care and comparable to the cohort with upfront Blina. The next GMALL trial will explore chemotherapy de-escalation based on risk stratification prospectively.
The GMALL Trial 08/2013 was funded by Deutsche Krebshilfe (111440)
