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

Sponsor
Assistance Publique - Hôpitaux de Paris
Study ID
NCT06860269
Phase
PHASE2/PHASE3
Status
Recruiting
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Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - 65 Years
Healthy Volunteers
Not accepted

Interventions

  • Randomization + Blinatumomab + chemotherapy — DRUG
    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)
  • Randomization + Standard frontline T-ALL chemotherapy backbone — OTHER
    Rando 3 : standard of care
  • Randomization + Isatuximab + Standard frontline T-ALL chemotherapy backbone — DRUG
    Rando 3 : ISA will be given at 10 mg/kg IV for a maximum of 28 infusions starting at induction up to maintenance phase.
  • Randomization + Blinatumomab + Ponatinib + chemotherapy — DRUG
    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.
  • Randomization 1 + Allo HSCT — OTHER
    Rando 1 : standard of care - Allogeneic Hematopoietic Stem Cell Transplantation
  • Randomization 2 + Allo HSCT — OTHER
    Rando 2 : standard of care

Study Details

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.

Key Dates

First listed
Mar 6, 2025
Start date
May 6, 2025
Status verified
Feb 2026
Primary completion
Mar 15, 2035
Completion
Mar 15, 2035

Study Design

Enrollment
1,200 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • No Intervention: GRAALL-2024/B Very High Risk - SOC
    Phneg BCP-ALL cohort Standard of Care : ALLO HSCT
  • Active Comparator: GRAALL-2024/B High Risk - SOC
    Phneg BCP-ALL cohort
  • Experimental: GRAALL-2024/B High risk - Blina
    Phneg BCP-ALL cohort
  • No Intervention: GRAALL-2024/B Standard Risk - SOC
    Phneg BCP-ALL cohort Standard of Care : Blinatumomab + chemotherapy
  • Active Comparator: GRAALL-2024/T - SOC
    T-ALL cohort
  • Experimental: GRAALL-2024/T - Isa
    T-ALL cohort
  • No Intervention: GRAAL-2024/T - T-cell lymphoblastic lymphoma - SOC
    Non randomized - standard care
  • Active Comparator: GRAAPH-2024 - SOC
    Phpos ALL cohort
  • Experimental: GRAAPH-2024 - Blina/Pona
    Phpos ALL cohort

Primary Outcome Measure

Overall survival [ Time Frame: At 5 years ]

Central Contacts

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