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 - Université de Picardie Jules Verne Accéder directement au contenu
Article Dans Une Revue Blood Année : 2022

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

1 AP-HP - Hopital Saint-Louis [AP-HP]
2 URP_3518 - Recherche clinique appliquée à l'hématologie
3 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)
4 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
5 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
6 CHU Bordeaux
7 CHU Angers - Centre Hospitalier Universitaire d'Angers
8 CHU UCL Namur
9 HUG - Hôpitaux Universitaires de Genève
10 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
11 IPC - Institut Paoli-Calmettes
12 CHU Nantes - Centre Hospitalier Universitaire de Nantes
13 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
15 MOBIDIC - Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer
16 Dynamo - Dynamique moléculaire de la transformation hématopoïétique
17 IGR - Institut Gustave Roussy
18 Département d'hématologie [Gustave Roussy]
19 CHU Amiens-Picardie
20 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
21 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
22 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
23 Hôpital Henri Mondor
24 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
25 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
26 University hospital of Zurich [Zurich]
27 CHU Nice - Centre Hospitalier Universitaire de Nice
28 UniCA - Université Côte d'Azur
29 CHU Limoges
30 CHV - Centre Hospitalier de Versailles André Mignot
31 CHU Sart Tilman [Liege, Belgium]
32 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
33 TIMONE - Hôpital de la Timone [CHU - APHM]
34 AMU - Aix Marseille Université
35 CHU d'Angers [Département Urgences]
36 Coordination du Groupe GRAALL [CH Lyon-Sud]
37 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
38 Hôpital Necker - Enfants Malades [AP-HP]
Thibaut Leguay
  • Fonction : Auteur
Carlos Graux
  • Fonction : Auteur
Jean-Pierre Marolleau
  • Fonction : Auteur
  • PersonId : 887235
  • IdRef : 06981676X
Pascal Turlure
  • Fonction : Auteur

Résumé

Background 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. Results 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). Conclusions 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.

Dates et versions

hal-04020877 , version 1 (09-03-2023)

Identifiants

Citer

Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Hunault-Berger Mathilde, Carlos Graux, et al.. 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. Blood, 2022, 140 (Supplement 1), pp.112-114. ⟨10.1182/blood-2022-157903⟩. ⟨hal-04020877⟩
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