A 3-cohort Randomized Study Evaluating the Role of New Immunotherapeutic Agents and of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Frontline Therapy of Adults With Acute Lymphoblastic Leukemia

Phase 2

Not yet recruiting

• Conditions: Acute Lymphoblastic Leukemia
• Interventions: Other: Randomization 1 + Allo HSCT; Drug: Randomization + Blinatumomab + chemotherapy; Other: Randomization + Standard frontline T-ALL chemotherapy backbone; Drug: Randomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone; Other: Randomization 2 + Allo HSCT; Drug: Randomization + Blinatumomab + Ponatinib + chemotherapy

• Registration Number: NCT06860269
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-01-16
• Status Verified: 2025-02
• Study First Submitted QC: 2025-02-28
• Last Update Submitted: 2025-02-28
• Study First Posted: 2025-03-06
• Last Update Posted: 2025-03-06
• Study Start: 2025-03-15
• Primary Completion: 2035-03-15
• Study Completion: 2035-03-15

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 1200

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 exclusion criteria :

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. 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
6. Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation
7. Chronic pancreatitis or acute pancreatitis within 6 months before study start
8. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) or active infection with Hepatitis B or C.
9. Concurrent severe diseases which exclude the administration of therapy
10. Treatment with any other investigational agent or participating in another trial within 30 days prior to entering this study
11. Pregnancy and breast feeding
12. Patients unwilling or unable to comply with the protocol
13. Patients under a legal protection regime (guardianship, trusteeship, judicial safeguard)
14. Chronic or current active uncontrolled infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment
15. Current use of prohibited medication
16. Known hypersensitivity or severe reaction to ponatinib (GRAAPH), blinatumomab (GRAAPH and GRAALL-B) , isatuximab (GRAALL-T) or their excipients.
17. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GRAALL-2024/B High Risk - SOC	Randomization 1 + Allo HSCT	Phneg BCP-ALL cohort
GRAALL-2024/B High risk - Blina	Randomization + Blinatumomab + chemotherapy	Phneg BCP-ALL cohort
GRAALL-2024/T - SOC	Randomization + Standard frontline T-ALL chemotherapy backbone	T-ALL cohort
GRAALL-2024/T - Isa	Randomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone	T-ALL cohort
GRAAPH-2024 - SOC	Randomization 2 + Allo HSCT	Phpos ALL cohort
GRAAPH-2024 - Blina/Pona	Randomization + Blinatumomab + Ponatinib + chemotherapy	Phpos ALL cohort

Primary Outcome Measures

Name	Time	Method
Overall survival	At 5 years	For GRAAPH-2024 patients (phase 3) - Phpos ALL
Event-Free Survival	At 5 years	For GRAAL-2024/T patients (phase 3)

Secondary Outcome Measures

Name	Time	Method
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 4 months	After consolidation
Measurable residual disease (MRD) response	Up to 5 years	(IG/TR and BCR::ABL1 markers) At relapse
Measurable residual disease (MRD) response - non graft patients	Up to 6 months	(IG/TR and BCR::ABL1 markers) After each treatment cycle until maintenance (4 to 5 times)
Early mortality	At day 90
Measurable residual disease (MRD) response - 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
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	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