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362 First Results of the Risk-Adapted, MRD-Stratified GMALL Trial 08/2013 in 705 Adults with Newly Diagnosed Acute Lymphoblastic Leukemia/Lymphoma (ALL/LBL)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies I
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphoid Leukemias, ALL, Clinical Research, Clinically Relevant, Diseases, Lymphoid Malignancies
Sunday, December 12, 2021: 9:45 AM

Nicola Goekbuget, MD1, Matthias Stelljes, MD2, Andreas Viardot, MD3, Kathrin Nachtkamp, MD4*, Björn Steffen, MD5*, Folker Schneller, MD6*, Nael Alakel, MD7*, Max Topp8, Boris Böll, MD9*, Christoph Faul, MD10, Karsten Spiekermann, MD11, Knut Wendelin, MD12*, Maher Hanoun, MD, PhD13*, Ralph Wäsch14, Joachim Beck, MD15*, Sonja Martin, MD16*, Vladan Vucinic, MD17*, Claudia D. Baldus, MD18*, Monika Brüggemann, Prof., PhD19*, Thomas Burmeister, MD20*, Heike Pfeifer, MD21*, Stefan Schwartz, MD22*, Lena Baumann5*, Diana Tichy, PhD23*, Hubert Serve, MD5 and Walter Fiedler, MD24

1Department of Medicine II, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany
2Department of Medicine A, Hematology, Oncology and Pneumology, University of Muenster, Muenster, Germany
3Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
4Dept. of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
5Department of Medicine II, Hematology/Oncology, Goethe University, University Hospital, Frankfurt, Germany
6Medical Department III, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
7University of Dresden, Dresden, DEU
8Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
9Hematology/Oncology, University Hospital Cologne, Cologne, NRW, Germany
10Internal Medicine II, University Hospital and Comprehensive Cancer Center Tübingen, Universitätsklinikum Tübingen, Tübingen, Germany
11Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
12Klinikum Nuernberg, Paracelsus Medizinische Privatuniversität, Nuernberg, Germany
13Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
14Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
15Universitatsmedizin Mainz, Mainz, Schkeuditz, Germany
16Department of Hematology and Oncology, Robert-Bosch-Hospital, Stuttgart, Germany
17Clinic and Policlinic for Hematology and Cellular Therapy, University of Leipzig Medical Center, Leipzig, Germany
18Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany
19Medical Department II, Laboratory of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany
20Department of Hematology / Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany
21Klinikum der Goethe University, Department of Hematology, Frankfurt am Main, DEU
22Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
23Division of Biostatistics, German Cancer Research Center Heidelberg, Heidelberg, Germany
24Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Hospital Eppendorf, Hamburg, Germany

In the past decade outcome of adult ALL was improved significantly using pediatric-based chemotherapy in combination with risk-adapted stem cell transplantation (SCT) and targeted therapies. The GMALL Trial 08/2013 (NCT02881086) for patients (pts) aged 18-55 years (yrs) with newly diagnosed ALL/LBL has a BFM-based 2-phase induction, up to 8 cycles of PEG-asparaginase (ASP) with up to 7 cycles of HDMTX, HDAC, a reinduction phase and conventional maintenance up to 2.5 yrs. Two cycles Nelarabine are implemented for standard risk (SR) T-ALL. Pts with B-precursor-ALL (B-ALL) receive Rituximab independent of CD20 expression (Ph+ only if CD20+). Ph+ ALL pts receive Imatinib and a dose reduced induction (Vincristine, Dexamethasone, ASP). ASP is scheduled in induction 1 (IP1) (d 20) and 2 (d 34 for Ph+ and d 44 for Ph-) and dose is adapted to risk factors for hepatotoxicity. Pts with BMI>30 and/or liver steatosis receive 500 U/m2, whereas 2000 U/m2 is the standard dose. It is recommended to withhold the 2nd dose of ASP in case of clinically relevant ASP-associated toxicities. Pts with high-risk (HR) features (WBC > 30,000/µl in B-ALL, pro B-ALL-, KMT2A rearrangement, early/mature T-ALL) or Ph+ ALL are considered for SCT in CR1 after 1st consolidation (C1). Pts with MolFail (table 1) after C1 are candidates for targeted therapy (Blinatumomab, Nelarabin) followed by SCT. Randomization (R) I evaluates CNS irradiation versus i.th. prophylaxis in B- ALL/LBL. R II compares SCT versus SR therapy in HR pts with MolCR after induction. Both randomizations are blinded and not available for analysis. The trial is ongoing and scheduled to recruit 950 pts.

Between 8/2017-4/2021 770 pts from 78 centers were included and 705 were evaluable. The median age was 35 (18-55) yrs, 638 had ALL (B,Ph-: 55%, Ph+: 20%, T: 25%,) and 67 pts LBL (B:12%; T:88%). For ALL the hematologic (Hem) CR rate after C1 was 93% and the MolCR Rate 61% (75% mol. response) (table 1). HemCR rate was 72% in LBL with 21% PR. PET CT was negative in half of the LBL PR cases. The lowest HemCR rate was observed in early T-ALL (83%) together with a MolCR rate of 45% (71% mol. response).

In Ph- pts 2000 U/m2 as first dose ASP was administered in 66%, 500 U/m2 in 24%, no ASP in 1% and other doses in 9%. In pts with Ph+ ALL the respective numbers were 61%, 21%, 6% and 13%. For the 2nd dose the numbers were 43%, 21%,13% and 22% for Ph- and 41%, 24%, 13% and 22% for Ph+ pts. Bilirubine increases grade III/IV were observed in Ph- ALL in 18% of the cases treated with 500 U/m2 vs 24% for 2000 U/m2. In Ph+ ALL the respective numbers were 5% vs 3%. GOT/GPT grade III/IV increases were observed 29% of Ph- ALL pts treated with 500 U/m2 vs 25% of those with 2000 U/m2. The respective numbers for Ph+ ALL were 24% and 40%.

At a median follow-up of 23 mo, the overall survival (OS) for all pts (N=705) was 88% and 76% at 1 and 3 yrs resp (subgroups see table 1). OS was correlated to age, 87%, 74%, 69% and 73% at 3 yrs for pts aged 18-25, 26-35, 36-45 and 46-55 yrs resp. SR T-ALL reached an OS of 86% at 3 yrs with a conventional and nelarabine based consolidation. 79% of pts with an indication for SCT were transplanted (64 sibling, 174 MUD). The OS of SCT pts after SCT was 75% at 3 yrs.

63 pts with MolFail became candidates for a targeted therapy, which was realized in 89% of the cases. The molecular response was evaluable in 51 pts and reached 55% (N=40) and 18% (N=11) after one cycle of Blinatumomab or Nelarabin resp. Pts with MolFail (N=63) achieved an OS of 84% at 1y and 72% at 3 years resp (71% for Ph- and 76% for Ph+).

This large, ongoing prospective multicenter trial provides promising preliminary results. This applies also to those aged 45-55 yrs underlining that adult pts beyond the variable AYA definitions can benefit from pediatric-based therapy. Intensive and individualized ASP therapy was feasible. Whereas high HemCR rates were observed in nearly all subgroups, MolCR rates ranged from 41-74% and a relevant proportion remained MRD low positive underlining the need for detailed MRD classification. MRD-based targeted treatment was realized in a high proportion of pts. Responses to Blinatumomab in MolFail were lower compared to previous trials. Responses to Nelarabine in MolFail T-ALL pts were only 18%. OS of MolFail pts however was promising with the combination of targeted therapy and SCT. Thus, SCT is still a key component, contributing to improved outcomes although the overall proportion of SCT was lower than in previous GMALL trials.

Funded by Deutsche Krebshilfe

Disclosures: Goekbuget: Astra Zeneca: Other: Invited talk for company sponsored symposia (with honor); Gilead/Kite: Consultancy; Abbvie: Other; Morphosys: Consultancy; Erytech: Consultancy; Incyte: Other: Research funding for Institution; Cellestia: Consultancy; Jazz Pharmaceuticals: Other: Research funding for institution; Pfizer: Consultancy, Other: Research funding for institution; Novartis: Consultancy, Other: Research funding for Institution; Amgen: Consultancy, Other: Invited talks for company sponsored symposia (with honoraria); Research funding for institution; Servier: Consultancy, Other. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nachtkamp: Jazz: Honoraria; Bsh medical: Honoraria; Celgene: Other: Travel Support. Topp: Novartis: Consultancy; Roche: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Macrogeniecs: Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Universitatklinikum Wurzburg: Current Employment. Wäsch: BMS/Celgene: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy. Vucinic: Abbvie: Honoraria, Other: Travel Sponsoring; MSD: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Brüggemann: Amgen: Other: Advisory Board, Travel support, Research Funding, Speakers Bureau; Incyte: Other: Advisory Board; Janssen: Speakers Bureau. Pfeifer: Incyte: Honoraria, Research Funding. Schwartz: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Other: Travel grants, Speakers Bureau; BTG International Inc: Membership on an entity's Board of Directors or advisory committees; MSD Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Basilea: Other: Travel grants; Gilead: Other: Travel grants, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Morphosys: Research Funding. Fiedler: Abbvie: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; Amgen: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material, Patents & Royalties, Research Funding; Ariad/Incyte: Honoraria; Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Other: Meeting attendance, Preparation of information material; MorphoSys: Consultancy, Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sanyko: Consultancy, Other: Meeting attendance, Preparation of information material; Stemline: Consultancy; Servier: Consultancy, Other: Meeting attendance, Preparation of information material.

OffLabel Disclosure: Nelarabine in newly diagnosed T-ALL

*signifies non-member of ASH