Paper Details

ABSTRACT

Background: Outcome in older patients (pts) with ALL has improved considerably with moderately intensive pediatric-based therapy with/ without first-line immunotherapy. However, limited data on this approach have been reported in larger, unselected patient populations.

Methods: The German Multicenter Study Group for Adult ALL (GMALL) conducted a clinical trial (age >55 yrs; NCT00198978), followed by a prospective registry (NCT02872987). Strategies were modified over the years (yrs). Backbone (2003-17): Pre-phase (Dexa, Cyclo), induction I (Dexa, VCR, idarubicin), induction II (Cyclo, AraC), repeated consolidation (C) cycles with IDMTX (±ASP), HDAC, reinduction (VCR, idarubicin, Cyclo, AraC), ± Rituximab (CD20+), intrathecal prophylaxis and maintenance (6-MP/MTX) (group 1). Next protocol (2017-23): added PEG-ASP to IDMTX and Blinatumomab (BLIN) for molecular failure (MolFail) after C2 (group 2). Latest protocol (2023-25): 3 BLIN cycles for all pts starting after C1, omitting one C cycle (group 3). The GMALL registry covers newly diagnosed ALL on a national population-based level and reflects the results of standard recommendations in Germany.  Overall Survival (OS) is reported at 3 yrs (groups 1/2) and 2 yrs (group 3). Molecular CR (MolCR), intermediate MRD (MolIMR) and MolFail were defined as MRD negative, MRD positive <0.01% and MRD positive ≥0.01%, respectively (resp), by quantitative PCR (clonal IG/TR rearrangements) in the central GMALL lab.

Objective: The goal of this analysis was to describe outcome in older ALL pts, evaluate prognostic factors and identify factors for improvement.

Results: 1244 evaluable pts from 150 sites were included (2003-2025). The median age was 67 (56-85) yrs. Age groups were 56-65 yrs (44%), 66-75 yrs (47%) and >75 years (9%), resp. 6% had a KMT2A rearrangement and 16% had pro-B ALL. The CR rate after induction was 80% with 11% early death (ED) and 9% failure, resp. MRD response data after consolidation I showed MolCR, MolIMR and MolFail in 57%, 14% and 29%, resp. OS for the total group was 36% at 3 yrs (58% at 2 yrs)

Age significantly affected CR rate (p<.0001) via rising ED: 7%, 12% and 23% for ages 56-65, 66-75 and >75 yrs. Charlson score also correlated with ED: 8%, 12% and 21% (p=.0007) for scores 0, 1-2 and ≥3.

In groups 1, 2 and 3 the number of evaluable pts was 547, 516 and 181, resp. After induction CR rates (77%, 83% and 83%) and MolCR rates (48%,46%,42%) were comparable. Death in CR was limited (4%, 4% and 1% resp). OS increased significantly from 45% to 59% and 70% (p<.0001) in the cohorts resp. Other significant prognostic factors for OS in the total cohort were subtype (34% vs 48% for Pro-B vs c/pre-B; p=.0002), leukocyte count ≤30,000/µL vs >30,000/µL (50% vs 33%; p<.0001), Charlson score (50%, 44% vs 38%; p=.001) and molecular response after consolidation I (MolCR vs IMR vs Fail 79%, 71% and 57%; p=.001) whereas BMI had no impact. A multivariate analysis (excluding molecular response) confirmed that leukocyte count, Charlson score and group were significant factors, whereas subtype was not significant.

OS at 2 yrs improved significantly across cohorts: ages 56-65 yrs (50%/65%/76%; p<.0001) and 66-75 yrs (45%/58%/75%; p=.0003). OS improved with WBC ≤30,000/µL (51%/61%/77%; p<.0001) but less with WBC >30,000/µL (20%/55%/51%; p<.0001). Pts with MolCR after C1 had OS of 76%/78%/96% (p=.02); MolIMR 45%/69%/94% (p>.05); MolFail 63%/51%/74% (p>.05). The rates of SCT in CR1 were 13%, 24% and 22% in cohorts resp. 

Conclusion: In a large prospective cohort of older patients mostly managed according to standard of care, the outcome improved considerably over the yrs by stepwise implementation of immunotherapy with Blinatumomab. Overall, the regimen including the GMALL chemotherapy backbone is well tolerated with low rates of death in CR. Remaining issues are induction therapy in pts older than 75 yrs and/or Charlson score ≥3 due to ED calling for earlier integration of immunotherapy either by use of Inotuzumab or Blinatumomab as phase II of induction. Further improvement is also required in high-risk pts. Since SCT is rarely offered in older pts in our practice, the outcome remained inferior compared to standard-risk pts even in cohort 3. Though longer follow-up is needed, these preliminary results underline the potential to improve OS in older pts by adding immunotherapy to an effective backbone, potentially reducing chemotherapy further. This will be evaluated in GMALL Trial 09.