Acute Lymphoblastic Leukemia
Conditions
Brief summary
Adult acute lymphoblastic leukemia (ALL) includes Ph-positive (Phpos) ALL, Ph-negative (Phneg) B-cell precursor (BCP) ALL and T-ALL/lymphoblastic lymphoma (LL), accounting for approximately 25, 50 and 25% of all cases, respectively. In younger adults, the results associated with standard therapy have markedly improved in these 3 groups, due to chemotherapy intensification in the BCP and T groups and addition of TKIs in the Phpos group, respectively. This led to reevaluate the role of allogeneic hematopoietic stem cell transplantation (HSCT) in first remission, which is generally now indicated only in higher-risk patients, mostly defined as those with persistent high levels of minimal residual disease (MRD). Nevertheless, event-free survival (EFS) remains at 60-70% at 3 years, meaning there is still room for further improvements. Fortunately, new immunotherapies have been approved to treat relapsed/refractory (R/R) BCP-ALL patients, including the anti-CD19 bispecific T-cell engager blinatumomab (BLINA, Blincyto®, Amgen). 4 BLINA is also approved for the frontline treatment of patients with persistent high measurable residual disease (MRD) levels after initial therapy (IG/TR MRD ≥0.1% (≥1.10-3 )). BLINA has been also evaluated frontline in combination with TKI in the Phpos group leading to promising outcome improvements. Toxicities associated with these combined treatments seem to be limited and manageable. In the Phpos ALL subset, the third-generation tyrosine kinase inhibitor ponatinib (PONA, Iclusig®, Incyte) has also been evaluated frontline with promising results when compared to 1st or even 2nd generation TKI. In the T-ALL/LL subset, anti-CD38 antibodies, approved to treat patients with multiple myeloma, are potential drugs of interest. The anti-CD38 antibody isatuximab (ISA, Sarclisa®, Immunogen, Sanofi-Aventis) is currently approved to treat myeloma patients in 2nd line. In vitro and in vivo preclinical studies suggest that CD38 is a relevant target in T-ALL and that isatuximab may be useful to eradicate residual disease in this subgroup of patients. Incorporation/combination of these new agents into frontline adult ALL therapy could allow reducing relapse incidence and prolonging survival in these patients, challenging the indication for HSCT in first complete remission (CR). The present GRAALL-2024 study is a prospective multicenter multi-country 3-cohort randomized clinical trial. The 3 cohorts are : GRAALL-2024/B : Phneg BCP-ALL GRAAPH-2024 : Phpos ALL GRAALL-2024/T : T-ALL/LL Eligible patients will be allocated to one on the 3 study cohorts during a common treatment prephase. The primary objective of the study is to improve the outcome of younger adults with ALL through optimal frontline incorporation of new antibody-based therapies, including BLINA in Phneg/pos BCP-ALL patients and ISA in T-ALL/LL patients, and to refine indication for allogeneic HSCT in first remission in Phneg/pos BCP-ALL patients.
Interventions
DRUGRandomization + Blinatumomab + chemotherapy
Rando 1 : BLINA will be given at 28 µg/day IVC from D1 to D28 for 2 to 4 cycles (first cycle starts with 9 µg/day for 7 days)
OTHERRandomization + Standard frontline T-ALL chemotherapy backbone
Rando 3 : standard of care
DRUGRandomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone
Rando 3 : ISA will be given at 10 mg/kg IV for a maximum of 28 infusions starting at induction up to maintenance phase.
DRUGRandomization + Blinatumomab + Ponatinib + chemotherapy
Rando 2 : * PONA will be given at 45 mg/day PO during 2 cycles, 30 mg/day during 2 additional cycles, and 15 mg/day during maintenance phase or after alloHSCT * BLINA will be given at 28 µg/day IVC from D1 to D28 for 2 to 5 cycles (first cycle starts with 9 µg/day for 7 days). Patients allografted will receive two courses before transplant.
OTHERRandomization 1 + Allo HSCT
Rando 1 : standard of care - Allogeneic Hematopoietic Stem Cell Transplantation
OTHERRandomization 2 + Allo HSCT
Rando 2 : standard of care
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
3-cohort stratified multicenter multi-country prospective open-label randomized Phase III trial. In each cohort, participants will be randomized according to a 1:1 ratio (R1, R2 and R3). Additionnally a phase 2 single arm trial will be performed in SR patients of the Phneg BCP-ALL cohort. Of note, T-LL patients will be included but not randomized to receive ISA or not.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Patients aged 18 to 65 years old 2. Newly diagnosed ALL or T-LL according to the WHO criteria 3. Immunophenotypic, cytogenetic and/or FISH and molecular evaluation performed and allowing classifying the patient in one of the Phpos ALL, Phneg BCP-ALL or T-ALL/LL cohorts 4. Not previously treated except with corticosteroids and/or intrathecal therapy (prephase) 5. Eligible for allo-HSCT if Phpos ALL or Phneg BCP-ALL 6. ECOG performance status ≤2 7. Patient willing and able to understand the protocol requirements and comply with the treatment schedule, scheduled visits, electronic patient outcome reporting, exams and other requirements of the study 8. Patients has signed written inform consent 9. Willingness of women of child-bearing potential (WOCBP) and male subjects whose sexual partners are WOCBP to use an effective form of contraception, i.e. methods with a failure rate of \<1% per year when used consistently and correctly, during the study and at least 6 months thereafter 10. Eligible for National Health Insurance (for French patients)
Exclusion criteria
Common
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | At 5 years | For GRAAL-2024/B HR patients (phase 3) |
| Event-Free Survival | At 5 years | For GRAAL-2024/T patients (phase 3) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival | At 5 years | in the T-ALL/LL cohorts |
| Event Free Survival | At 5 years | — |
| Relapse Free Survival | At 5 years | — |
| Hematological complete response rate | At 45 days | After induction |
| Measurable residual disease (MRD) response level | At inclusion | (IG/TR and BCR::ABL1 markers) at diagnosis |
| Measurable residual disease (MRD) response level - non graft patients | Up to 6 months | (IG/TR and BCR::ABL1 markers) After each treatment cycle until maintenance (4 to 5 times) |
| Measurable residual disease (MRD) response level - graft patients | Through study completion, approximately 5 years | (IG/TR and BCR::ABL1 markers) At day 100 post-HSCT and every 3 months post HSCT for patients receiving allo-HSCT during maintenance up to 2 years |
| Early mortality | At day 30 | — |
| Cumulative incidence of relapse (CIR) | At 5 years | — |
| Cumulative incidence of non relapse mortality | At 5 years | — |
| Transplant-related mortality (TRM) | At 5 years | For graft patients |
| Graft-versus-host-disease (GvHD) incidence | At 5 years | For graft patients |
| Number of patients who experience one or more Adverse Event (AEs) or Serious Adverse Event (SAEs) | At 5 years | — |
| Rate of patients who experience one or more Adverse Event (AEs) or Serious Adverse Event (SAEs) | At 5 years | — |
| Quality of life level | Until 5 years | Assessed with EQ5D 5L It evaluates five dimensions : mobility, self-care, usual activities, pain/discomfort and anxiety/depression and each dimension has five levels : no problems, slight problems, moderate problems, severe problems and extreme problems. Answers are given on a 5-point scale by domain, the higher the score, the poorer the quality of life. At each study visit |
| Incremental cost effectiveness and cost utility ratio | At 5 years | Defined as the difference in total costs divided by the difference in survival and in quality adjusted life years |
Countries
France
Contacts
CONTACTNicolas Boissel, MD PhD
CONTACTJérôme Lambert, MD PhD
Outcome results
None listed