Outcome of 841 Older Patients (>55 yrs) with Newly Diagnosed Ph/BCR-ABL Negative ALL Prospectively Treated According to Pediatric-Based, Age-Adapted GMALL Protocols

Outcome in younger patients (pts) with ALL has been improved considerably using intensive pediatric-based therapy, but limited data on this approach have been reported for older pts and even the age cut-off is heavily debated. The German Multicenter Center Study Group for Adult ALL (GMALL) has conducted a clinical trial (>55 years) (NCT00198978) which was followed by a registry trial based on standard management recommendations with prospective documentation in the GMALL registry (NCT02872987). Strategies were modified over the years (yrs). The backbone included: Pre-phase (Dexa, Cyclo), induction I (Dexa, VCR, Idarubicine), induction II (Cyclo, AraC), ±post-induction PEG-ASP, consolidation (C) cycles with IDMTX (± E.coli ASP), HDAraC (earlier: VM26), reinduction (VCR, Idarubicine, Cyclo, AraC), ± Rituximab in CD20+, i.th. prophylaxis and maintenance (6-MP/MTX) (group 1). The latest protocol (from 2017) additionally included IDMTX/PEG-ASP in consolidation and recommended MRD-based treatment modification (Blinatumomab in B-Lin and Nelarabin in T-Lin) in molecular failure (MolFail) after C2 (group 2). 882 patients (pts) from 142 sites were included 2003-2021 (table 1). 5% were withdrawn early and therefore not evaluable. The median age was 68 (56-86) yrs. 61% were older than 65 yrs. B-Lin-ALL was present in 68%; 7% of B-Lin-ALL (N=45) had a KMT2A-rearrangement. 19% and 9% had immature subtypes, pro-B and early T-ALL resp.. 50% had at least one comorbidity according to the Charlson-Score (ChS); 11% had a score ≥3; 28% had an BMI≥30 mg/m2. Group 2 vs group 1 had a significantly lower median age (66 vs 68 yrs; p=.001) and a higher proportion of T-ALL (21% vs 14%; p=.0003). In 841 pts the CR rate after induction was 73% with 14% early death (ED) and 13% failure. The ED rate was lower in group 2 vs group 1 (9% vs 15%; p=.04). CR rates were 76%, 73% and 63% in three age groups (56-65, 66-75, ≥76 yrs) with ED rates of 9%, 14% and 26% resp. (p<.0001). CR rates were significantly lower in pts with WBC ≥30.000/µl (table 1). BMI (≥30 kg/m2) was not associated to CR/ED but ED rates were correlated to ChS with a high ED rate (26%) in those with ChS ≥3 (table 1). MRD response data were available in 163, 239 and 173 pts after induction II, C1 and C2 resp. The molecular CR (MolCR)/ MolFail rates were 41%/52%, 57%/38% and 64%/30% resp. The remaining pts had intermediate MRD (MolIMR). MolCR rates were similar in B-Lin only (43%/58%/64%). With a median follow up of 2.7 yrs overall survival (OS) in 841 pts at 3, 5 and 10 yrs was 36%, 28% and 22% resp. The 3y remission probability was 37%. Mortality in CR was 5% (3%, 6% and 7% by age) and 12% of the pts were withdrawn from protocol. OS strongly correlated to age and was very poor in pts older than 75 yrs (7% at 3 yrs; table 1). Only 8% (N=51) of all CR pts received an allogeneic stem cell transplantation (SCT) in CR1 (N=20 ≥65 yrs) but the SCT-rate increased in group 2 vs group 1 (9% vs 5%). 3y-OS after SCT in this selected group (N=51) was 56%. OS was significantly superior in group 2 vs group 1 (50% vs 32%; p<0.001) (figure 1). This improvement occurred mainly in the younger age group (56-65 yrs): 62% vs 38% 3y OS in group 2 vs group 1 resp. (p<0.0001) with no significant improvement in pts older than 65 yrs. WBC and ChS≥3 were associated with poorer OS (table 1). MRD response had a significant impact on OS at all timepoints. Pts with MolCR after C1 had a 3 yr OS of 80% vs 52% for MolFail and 62% for MolIMR (p=.0004). Interestingly the 3y-OS of 52 MolFail pts tended to be superior in group 2 (74% vs 46%;p>.05). The CR rate and OS of MLL-rearranged cases was 62% and 19% resp. With this age-adapted, pediatric-based regimen a reasonable CR rate was achieved up to 75 yrs. Pt numbers were small and OS very poor in pts >75 yrs. MolCR rates were overall lower compared to more intensive protocols in younger pts. Thus, treatment modification based on MolFail is a promising approach and might produce benefits in many older pts. The optimal time-point for treatment change remains to be defined. Together with more intensive consolidation including PEG-ASP this modification likely contributed to the improved outcome with 62% OS in the youngest cohort (56-65 yrs) in group 2. In all older pts, but specifically in those >65-75 yrs or with multiple comorbidities, alternative protocols with targeted therapies and further step-wise reduction of chemotherapy require prospective exploration in clinical trials with the major goal to reduce ED rate and to improve MRD response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal