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

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Optimal Frontline Treatment for ALL
Hematology Disease Topics & Pathways:
ALL, Lymphoid Leukemias, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023: 4:00 PM

Nicola Goekbuget, MD1, Björn Steffen, MD2*, Kathrin Nachtkamp, MD3*, Boris Böll, M.D.4*, Veit L. Buecklein, MD5*, Christoph Faul, MD6, Jens Panse, MD7, Christoph Röllig, MD, MSc8*, Folker Schneller, MD9*, Bernd Spriewald, MD10*, Matthias Stelljes, MD11, Max S. Topp, MD12*, Andreas Viardot, MD PhD13, Vladan Vucinic, M.D.14*, Knut Wendelin, MD15*, Monika Brüggemann, MD16*, Monika Szczepanowski16*, Stefan Schwartz, MD17*, Thomas Burmeister, MD, PhD17*, Axel Benner18*, Nicholas Schreck18*, Lena Reiser1*, Hubert Serve, MD1 and Walter Fiedler, MD19

1Department of Medicine II, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany
2Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
3Dept. of Hematology, Oncology and Clinical Immunology, Düsseldorf University Hospital, Düsseldorf, Germany
4Department of Internal Medicine I, University Hospital, Cologne, Germany
5Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
6Department of Internal Medicine II, Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
7Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
8Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
9Klinikum Rechts der Isar der TU München, Munich, Germany
10Department of Medicine 5, University Hospital of Erlangen, Erlangen, Germany
11University of Muenster, Muenster, Germany
12Universitätsklinikum Würzburg, Würzburg, Germany
13Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
14Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig, Leipzig, Germany
15Med Clinic 5, Klinikum Nürnberg, Nuernberg, Germany
16Clinic for Internal Medicine II - Haematology, Oncology, University Clinic Schleswig-Holstein, Kiel, Germany
17Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin) Charité - Universitätsmedizin Berlin, Berlin, Germany
18Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
19University Hospital Hamburg-Eppendorf, Hamburg, DEU

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/m2 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.

Disclosures: Goekbuget: Servier: Honoraria, Research Funding; Clinigen: Honoraria, Research Funding; Autolus: Honoraria; Incyte: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Gilead: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Nachtkamp: BMS: Honoraria; Jazz: Honoraria. Böll: Novartis: Other: Support for attending meetings; Gilead: Honoraria, Other: Support for attending meetings; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Buecklein: Miltenyi Biotech: Research Funding; Pierre Fabre: Other: Travel Funding; Roche: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy; BMS: Research Funding; Gilead/Kite: Other: Travel Funding, Research Funding; Priothera: Consultancy. Panse: Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy; BMS: Consultancy; Alexion, AstraZeneca Rare Disease: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Ltd: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SOBI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Samsung Bioepis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd,: Membership on an entity's Board of Directors or advisory committees, Other: Third party writing assistance by Akshaya Srinivasan, PhD, of MediTech Media Ltd and funded by F. Hoffmann-La Roche Ltd, , Speakers Bureau; Apellis Pharmaceuticals, Inc.: Consultancy; Amgen: Consultancy. Röllig: Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria. Topp: Bristol Myers Squibb: Consultancy, Research Funding; Roche: Consultancy, Research Funding; GenMab: Consultancy; Takeda: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Other: Travel support; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding. Viardot: F. Hoffmann-La Roche Ltd, Abbvie, Kite/Gilead, BMS: Honoraria; F. Hoffmann-La Roche Ltd, Abbvie, Kite/Gilead, BMS: Consultancy; BMS: Research Funding. Brüggemann: Pfizer: Speakers Bureau; Janssen: Speakers Bureau; BD: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Schwartz: Pfizer: Consultancy, Honoraria; Amgen: Other: Advosory Board; Protherics: Research Funding. Benner: Sanofi: Other: Travel, Accomondations, Expenses. Fiedler: Amgen: Consultancy, Other: Support for meeting attendance, Patents & Royalties; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria, Other: Support in medical writing; Servier: Consultancy, Other: Support for meeting attendance; Morphosis: Consultancy; Stemline: Consultancy; Clinigen: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Support for meeting attendance; Apis: Research Funding.

OffLabel Disclosure: Blinatumomab

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