CNS Irradiation in Adult De Novo B-Precursor ALL / Lbl: Results of the Randomized GMALL T rial 08/2013 Indicate Potential Antileukemic Efficacy

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL is a pediatric based regimen with MRD based treatment stratification and risk adapted stem cell transplantation (SCT) (Gökbuget et al, ASH 2021). CNS prophylaxis consisted of three doses i.th. MTX during induction II, 11 doses of triple i.th. for standard risk (SR) in consolidation (C)/maintenance and 1 dose before SCT in high risk (HR); 7 vs 1 cycle of HDMTX (1.5 g/m ² as 24h infusion) were scheduled in SR and HR resp. Prophylactic fractionated CNS irradiation (RAD) with 24 Gy during induction II (IP2) was part of all previous GMALL trials.

The trial incorporated a randomization for Ph/BCR::ABL1 negative (Ph-) B-precursor ALL/LBL without initial CNS involvement and treated until C1 in order to compare standard IP2 with i.th. MTX with vs without CNS RAD. The key endpoint was the time from start of induction to start of C1 in CR pts, reasoning that less toxicities and treatment delays would occur without CNS RAD. Further endpoints were remission duration (RD), event-free survival (EFS) and cognitive disturbances (DemTect Test). The statistical assumption was that it is possible to detect a shortening of time to C1 from 74 to 69 days with a power of more than 90% with 215 pts per arm with a two-sided α-niveau of 5%.

Between 8/2016-8/2022 1023 pts from 78 centers were included. 512 pts had Ph- B-precursor ALL/LBL (497/15). 31 pts had initial CNS involvement (N=20) or were not randomized due to other reasons (N=11). 241 pts were randomized in arm A (RAD) and 241 in arm B (NoRAD). The median age was 33.5 (18-55) yrs; c/pre B-ALL versus pro B-ALL was present in 83% vs 17%. 191 were HR vs 291 SR. No significant differences were observed between both arms.

477 pts were randomized (ITT population) and 422 were eligible (analysis population) since they achieved CR and were treated until C1. Reasons for non-eligibility were protocol violation (N=5), early death (ED) (N=15), withdrawal (N=12), no CR before C1 (N=18) and late withdrawals in CR before C1 (N=10). 207 pts in the RAD-arm (86%) vs 215 pts in the NoRAD-arm (89%) were eligible.

In the analysis population treatment per randomization was 97% in NoRAD and 95% in RAD arm. CR rates before C1 (95% RAD vs 96% NoRAD), ED rates (5% vs 4%), rates of grade III/IV leukopenia in IP2 (14% vs 16%) and infections (29% vs 29%) were similar. The median time to C1 was similar too (75 vs 76 days; p=0.34).

Relapse rates (RR) were lower in RAD (13%) vs NoRAD (18%) (p=0.14). Whereas CNS relapses were infrequent in both arms (N=1 vs N=3 i.e. 1% vs 1%; p=0.62), the rate of BM±other relapses (11% vs 15%; p=0.15) was lower in the RAD arm. The cumulative incidence of CNS relapse at 3 yrs was 1% vs 1% and of all relapses 14% vs 20% (p=0.13).

The EFS at 3 yrs was higher for the RAD (79% [95%-CI: 72% - 85%]) vs NoRAD (72% [95%-CI: 65% - 78%])(p=0.10) in the analysis population and 74% vs 67% (p=0.13) in the ITT population. In the ITT population the impact was statistically significant (p=0.05) in SR pts whereas no difference was detected in HR (i.e. pts with indication for SCT) (figure 1); differences did not reach significance in the analysis population.

We further analyzed the impact of randomization arm on cognitive function (analysis population). After C1 results were available in 264 pts. In the RAD vs NoRAD arm 2% vs 2% resp. had low scores (0-8) and 10% vs 8% intermediate scores (9-12) indicating a relevant or limited cognitive disturbance. At the end of therapy (week 130), results are available in 53 pts treated in SR arm. 0% vs 4% had low and 4% vs 4% intermediate scores. Thus, relevant cognitive limitations were present in both arms.

The primary endpoint (time to C1) was not met. Pts with RAD did have a trend towards better EFS and RD. The CNS RR was overall low but CNS RAD might have an impact on the systemic relapse rate in SR pts. We recorded no significant negative impact of CNS RAD on DemTect results, but this requires further observation. Results must be interpreted in the context of adult pts with potentially lower risks for cognitive disturbances compared to children and - on the other hand - a relatively low dose of systemic HDMTX. Overall, no clear negative effects of CNS RAD were detected whereas a trend towards positive impact on EFS was observed.

GMALL 08/2013 is an independent academic trial funded by the Deutsche Krebshilfe.