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50 In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival – Results from the Graall-2014 Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Management of Novel ALL Subsets in Different Age Groups
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Biological therapies, Clinical Research, Combination therapy, Diseases, Therapies, therapy sequence, Lymphoid Malignancies, Transplantation, Minimal Residual Disease
Saturday, December 10, 2022: 9:45 AM

Nicolas Boissel, MD, PhD1,2, Francoise Huguet, MD3*, Thibaut Leguay, MD4*, Hunault-Berger Mathilde, MD, PhD5*, Carlos Graux6*, Yves Chalandon, MD7, Eric Delabesse, MD, PhD8*, Yosr Hicheri, MD9*, Patrice Chevallier, MD10, Marie Balsat11*, Cedric Pastoret, MD, PhD12*, Martine Escoffre-Barbe, MD13*, Florence Pasquier, MD, PhD14*, Jean-Pierre Marolleau, MD, PhD15, Anne Thiebaut-Bertrand16*, Anne Huynh17*, Nathalie Dhedin, MD18*, Emilie Lemasle, MD19*, Caroline Bonmati, MD20*, Sébastien Maury21*, Gaëlle Guillerm, MD22*, Anna Berceanu, MD23*, Urs Schanz, MD24, Thomas Cluzeau, MD, PhD25, Pascal Turlure, MD26*, Philippe Rousselot, MD, PhD27*, Bernard J. M. De Prijck, MD28*, Nathalie Grardel, MD29*, Marie C Bene, PharmD, DPhil30*, Marine Lafage, MD31*, Norbert Ifrah, MD PhD32, Veronique Lheritier33*, Vahid Asnafi, MD, PhD34,35*, Emmanuelle Clappier, PharmD, PhD36* and Herve Dombret, MD PhD37,38

1St-Louis Hospital, APHP, Adolescent and Young Adult Hematology Department, Paris, France
2URP-3518, Saint-Louis Research Insitute, Université Paris Cité, Paris, France
3Department of Hematology, Institut Universitaire du Cancer-Oncopole CHU de Toulouse, Toulouse, France
4Hematology Clinic, Bordeaux University Hospital, Pessac, France
5department of hematology, CHU Angers, Angers, ML, France
6Université Catholique de Louvain, CHU UCL Namur (Godinne), Yvoir, Belgium
7Geneva University Hospitals, Geneva, Switzerland
9Departement d'Hematologie, Institut Paoli-Calmettes, MARSEILLE, France
10Hematology Department, Nantes University Hospital, Nantes, France
11Service Hematologie, Centre Hospitalier Lyon Sud, Lyon, France
12INSERM U1236 /Hematology Laboratory, University Hospital of Rennes, RENNES, FRA
13Hôpital de Pontchaillou, Centre Hospitalier Universitaire de Rennes, Rennes, France
14Gustave Roussy, Département clinique d'hématologie, INSERM UMR1170, Villejuif, FRA
15Hematology Department, Amiens University Hospital, Amiens, France
16Department of Hematology, CHU-Grenoble Onco-Hematologie, Grenoble, France
17Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
18St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
19Hematology Department, Henri-Becquerel Cancer Center, Rouen, France
20Service D'Hématologie, Centre Hospitalier Universitaire De Nancy, Nancy, FRA
21Service d’Hématologie clinique, Hôpitaux universitaires Henri-Mondor (AP-HP), Créteil, FRA
22Department of Hematology, Brest University Hospital, Brest, France
23Clinical Hematology, Besançon University Hospital, Besançon, France
24Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
25Département d'Hématologie Clinique, Université Côte d'Azur, CHU Nice, Nice, Provence Alpes Cote d'Azur, France
26Department of Clinical Hematology, Limoges University Hospital, Limoges, France
27Hematology Department, Centre Hospitalier de Versailles, LE CHESNAY CEDEX, France
28CHU Sart Tilman, Liege, BEL
29Laboratory of Hematology, Centre Hospitalier Universitaire Lille, Lille, France
30Hematology Biology, Nantes University Hospital, Nantes, France
31Department of Genetics, La Timone Hospital, Aix Marseille University, MARSEILLE, France
32Clinical Hematology, Angers University Hospital, Angers, France
33Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), Centre Hospitalier Lyon Sud, Lyon, France
34INSERM U1151, Université Paris Descartes Sorbonne Cité, Paris, France
35Laboratory of Onco-Hematology, Necker University Hospital, Paris, France
36Hematology Laboratory, AP-HP, Hôpital Saint-Louis, Paris, France
37URP-3518, Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
38Hopital Saint-Louis, Assistance Publique - Hopitaux De Paris (AP-HP), Paris, FRA


During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.

In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.

Patients & Methods

A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.


Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).

Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p<0.001), especially in pts aged 18-44y (21 vs 40%, p<0001). Consequently, the rate of pts transplanted in CR1 dropped down from 38 to 23% (p<0.001).

The GRAALL-2014 strategy also yielded a significant reduction in CITRM (5 vs 11% at 3 years; p<0.001; Figure 1B) after CR achievement. This reduction was more pronounced in pts aged 45-59y (7 vs 17%, p<0.001 compared to 4 vs 8%, p= 0.02 in 18-44y pts). This was associated with an increased CIR (35% vs 28% at 3 years; p= 0.01), with more late relapses as depicted in Figure 1A. Even if the resulting RFS was similar in both cohorts (59 vs 62% at 3 years; p= 0.77), OS was significantly longer in the GRAALL-2014 (71 vs 64%; p= 0.002) (Figure 1C) likely due to better post-relapse outcomes. When censoring those GRAALL-2014 pts who received nelarabine or blinatumomab in CR1, observations were basically unchanged, even if the difference in CIR was even more marked.

Finally, using a 3-month RFS landmark in the 211 GRAALL-2014 pts eligible for HSCT in CR1 based on their poor early MRD response, HSCT significantly prolonged RFS (HR= 0.46 [95% CI, 0.27-0.78]; p= 0.004).


In adults with Ph-negative ALL enrolled in the GRAALL-2014, age-adapted chemotherapy intensity and MRD-driven indication for HSCT significantly reduced induction and post-remission TRM. This translated into a prolonged OS, indicating that this strategy was safe, despite a higher incidence of late relapses. Newly available salvage options along with HSCT in CR2 might also have played a role.

Disclosures: Boissel: GILEAD: Honoraria; AMGEN: Honoraria; ARIAD/INCYTE: Honoraria; ASTELLAS: Honoraria; NOVARTIS: Honoraria; SERVIER: Honoraria. Huguet: novartis: Honoraria; incyte: Honoraria; bms: Honoraria; amgen: Honoraria; pfizer: Honoraria; jazz pharma: Honoraria. Leguay: Servier: Consultancy; Amgen: Consultancy. Mathilde: Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chalandon: Abbvie: Other: consulting fees + travel support; Roche: Other: consulting fees + travel support; Incyte: Other: consulting fees + travel support; Amgen: Other: consulting fees + travel support; Astra-Zeneca: Other: consulting fees + travel support; MSD: Other: consulting fees+ travel support; Novartis: Other: consulting fees; BMS: Other: consulting fees; Pfizer: Other: consulting fees; Gilead: Other: consulting fees + travel support; Jazz: Other: consulting fees+ travel support; Servier: Other: consulting fees; Janssen: Other: Travel support. Chevallier: Incyte: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Jazz Pharmaceuticals: Honoraria. Cluzeau: BMS/Celgene, Novartis, Jazz: Consultancy, Speakers Bureau; AbbVie, Astellas, Servier: Speakers Bureau. Rousselot: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

*signifies non-member of ASH