Comparing new immunotherapies and donor stem cell transplant as first treatment for adults with acute lymphoblastic leukemia

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

This study will test whether adding newer immunotherapy drugs and/or using donor stem cell transplant up front improves outcomes for adults (18–65) newly diagnosed with acute lymphoblastic leukemia.

Quick facts

• Phase: Phase2; Phase3
• Study type: Interventional
• Enrollment: 1200 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (Academic / other)
• Drugs / interventions: blinatumomab, isatuximab, ponatinib, chemotherapy
• Locations: 1 site (Paris)
• Trial ID: NCT06860269 on ClinicalTrials.gov

What this trial studies

This randomized phase 2/3 study enrolls adults (18–65) with newly diagnosed acute lymphoblastic leukemia grouped into three cohorts: Ph-positive, Ph-negative B‑cell precursor, and T‑ALL/lymphoblastic lymphoma. Within each cohort, patients are randomized to standard intensive chemotherapy backbones with or without added immunotherapies (blinatumomab or isatuximab), and, for Ph‑positive patients, combinations that include the TKI ponatinib; one randomization also compares planned allogeneic hematopoietic stem cell transplantation in first remission. Treatment decisions and consolidation with allo‑HSCT are informed by response and minimal residual disease (MRD) levels, and key endpoints include event‑free survival, overall survival, and relapse rates across arms. The study is led by Assistance Publique–Hôpitaux de Paris and conducted at Hôpital Saint Louis in Paris as a multicohort randomized effort to improve frontline outcomes.

Who should consider this trial

Good fit: Adults aged 18–65 with newly diagnosed ALL or T‑LL who can be classified as Ph‑positive, Ph‑negative BCP‑ALL, or T‑ALL/LL, who have ECOG ≤2, have not received prior therapy beyond steroids or intrathecal treatment, and who can comply with study procedures are the ideal candidates.

Not a fit: Patients over 65, those who have already received substantial prior therapy, those with poor performance status or major comorbidities that prevent intensive chemotherapy or HSCT, or those unable to travel to the Paris site are unlikely to be eligible or to benefit.

Why it matters

Potential benefit: If successful, this approach could increase cure rates and reduce relapses by incorporating effective immunotherapies and targeted agents into initial treatment and better selecting patients for donor transplant.

How similar studies have performed: Components of this approach—blinatumomab and TKIs—have improved outcomes in relapsed/refractory and Ph‑positive ALL, but randomized frontline combinations with agents like isatuximab and systematic allo‑HSCT comparisons are more novel and still being defined.

Eligibility criteria

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

Where this trial is running

Paris

• Hôpital Saint Louis — Paris, France (Recruiting)

Study contacts

• Study coordinator: Nicolas Boissel, MD PhD

Conditions Acute Lymphoblastic Leukemia