GRAALL-2024

L’objectif est d’améliorer la survie des patients grâce à l’introduction précoce d’une immunothérapie (blinatumomab pour les LAL B, anti-CD38 pour les LAL T) et à l’affinement des critères d’indication d’allogreffe de cellules souches hématopoïétiques.

GRAALL-2024/B
o HR patients (phase 3) : To improve the outcome of younger adults with HR Ph-negative BCP-ALL through early frontline incorporation of subcutaneous blinatumomab and refined indications for allogeneic HSCT.
o SR patients (phase 2) : To improve the outcome of younger adults with SR Ph-negative BCP-ALL through frontline incorporation of subcutaneous blinatumomab.

GRAALL-2024/T (phase 3) : To improve the outcome of younger adults with T-ALL through early frontline incorporation of isatuximab

GRAAPH-2024 (phase 3) : To improve the outcome of younger adults with Phpositive B-ALL through early frontline incorporation of subcutaneous blinatumomab, ponatinib, and refined indications for allogeneic HSCT.

Safety profiles.
Patient-related outcomes (PROs) and quality-of-life (QoL).
Cost effectiveness and utility.

The GRAALL-2024/B sub-study will include patients with Phneg BCP-ALL :
BLINA will be given at 500 μg SC QD for D1 to D7 and then 1000 μg SC TIW from D8 to D26, for the first course. Three additional cycles will be given at 1000 μg SC TIW from D1 to D26 Patients allografted will receive a minimum of 2 courses and an optional course in bridge to transplant.

The GRAALL-2024/T sub-study will include patients with T-ALL/LL :
ISA will be given at 10 mg/kg IV for a maximum of 28 infusions starting at induction up to maintenance phase.

The GRAAPH-2024 sub-study will include patients with Phpos ALL :
– 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 500 μg SC QD for D1 to D7 and then 1000 μg SC TIW from D8 to D26, for the first course. Four additional cycles will be given at 1000 μg SC TIW from D1 to D26. Patients allografted will receive two courses before transplant.

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 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 document.
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).

1. Patient previously treated with systemic chemotherapy, antibody-based therapy or TKI.
2. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
3. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, coordination/movement disorder, autoimmune disease with CNS involvement, psychosis (with the exception of CNS leukemia that is well controlled with intrathecal therapy).
4. Patients with LVEF<50% or other clinically significant heart disease (e.g.unstable angina, congestive heart failure, uncontrolled hypertension).
5. If patients with Phpos ALL :
   1. Complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bi-fascicular block.
   2. History of or presence of clinically significant ventricular or atrial tachyarrhythmias.
   3. Clinically significant resting bradycardia (< 50 beats per minute).
   4. Congenital long QT syndrome or QTcF > 470 msec on screening ECG. If QTc > 470 msec and electrolytes are not within normal ranges before ponatinib dosing, electrolytes should be corrected and then the patient rescreened for QTcF criterion.
   5. Currently taking drug(s) that are known to have a risk of causing prolonged QTc or TdP unless the drug(s) can be changed to acceptable alternatives (ie, an alternate class of agents that do not affect the cardiac conduction system), or the participant can safely discontinue the drug(s).
   6. Previous myocardial infarction within the last 12 months.
   7. Symptomatic peripheral vascular disease.
   8. History of ischemic stroke or transient ischemic attacks (TIAs) within the last 12 months.
   9. Significant bleeding disorder or thrombophilia unrelated to the underlying malignancy indication for study participation.
   10. Gastrointestinal disorders, such as malabsorption syndrome or any other illness that could affect oral absorption.
6. Prior documented chronic liver disease. Inadequate hepatic functions defined as AST or ALT > 5 x the institutional upper limit of normal (ULN), or >
   5 x ULN unless if considered due to leukemia. Total bilirubin > 1.5 x ULN unless if considered due to leukemia or Gilbert/Meulengracht.
7. Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation.
8. Chronic pancreatitis or acute pancreatitis within 6 months before study start.
9. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
10. Concurrent severe diseases which exclude the administration of therapy.
11. Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study.
12. Pregnancy and breast feeding.
13. Patients unwilling or unable to comply with the protocol.
14. Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard).
15. Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
16. Current use of prohibited medication (see Section 7.11).
17. Known hypersensitivity or severe reaction to ponatinib or excipients of ponatinib.
18. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study.

Lancement de l’étude : Juin 2025
Fin estimée des inclusions : Juin 2030
Nombre de patients à inclure : 1200 patients will be included, 600 Phneg BCP-ALL, 300 T-ALL/LL, ,and 300 Phpos BCPALL.

Pr Nicolas BOISSEL – Hôpital Saint-Louis (AP-HP)

Assistance Publique – Hôpitaux de Paris (AP-HP)