Acute Myeloid Leukemia, Fit Patients, FLT3 Internal Tandem Duplication Positive, Intermediate Risk Acute Myeloid Leukemia
Conditions
Keywords
acute myeloid leukemia, FLT3-ITD, Intermediate Risk, Fit, Gilteritinib, Deep molecular remission
Brief summary
This clinical trial aims to evaluate whether molecular MRD-guided chemotherapy can effectively treat FLT3-ITD mutated AML and potentially replace allogeneic hematopoietic stem cell transplantation. It primarily seeks to answer: * What is the complete remission rate after initial induction with Gilteritinib, Venetoclax, and Azacitidine? * What are the survival rates and safety of subsequent high-dose cytarabine consolidation after two cycles of this induction therapy? As a single-arm study, outcomes will be compared against historical data from standard treatments (including transplant) to assess if the new strategy is equally or more effective. Participants will: * Undergo three cycles of high-dose cytarabine consolidation after two cycles of induction therapy, contingent upon achieving deep FLT3-ITD molecular remission. * Start Gilteritinib maintenance therapy after consolidation if FLT3-ITD remains detectable, continuing until deep molecular remission is achieved again.
Detailed description
This single-center, phase II trial evaluates a novel, transplant-sparing strategy for fit patients with newly diagnosed intermediate-risk acute myeloid leukemia (AML) harboring FLT3-ITD mutations. The central hypothesis is that achieving deep molecular remission-as measured by a highly sensitive assay termed "DeepScan" (Levis et al., Blood 2022)-can identify a subset of patients who may attain long-term survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapeutic strategy consists of a sequential three-phase approach: Induction: Initial therapy combines the FLT3 inhibitor gilteritinib with venetoclax and azacitidine (the GVA regimen). This synergistic approach targets leukemia through concurrent inhibition of FLT3 and BCL-2 pathways, aiming to achieve high rates of complete remission and deep molecular clearance. Consolidation: Patients who achieve deep FLT3-ITD negativity, as assessed by the "DeepScan" minimal residual disease (MRD) assay after induction therapy, will proceed to consolidation with high-dose cytarabine (2 g/m² twice daily for 3 days) for three cycles, concurrently with gilteritinib. Maintenance: Patients maintaining deep FLT3-ITD negativity will receive gilteritinib monotherapy at 120 mg daily for 3 months. Those with detectable mutations will be withdrawn from the study. A key innovation of this trial is the implementation of "DeepScan," a next-generation sequencing-based assay co-developed with Professor Levis's team. This method detects FLT3-ITD mutations with a sensitivity of up to 10-⁶, surpassing conventional MRD monitoring techniques. It is designed to accurately define a state of deep molecular remission, which serves as the primary biomarker for directing patients toward a transplant-free pathway. This study challenges the current standard of care, in which allo-HSCT is frequently recommended. By prospectively assessing whether deep molecular responses-induced and maintained through this targeted and chemotherapy-inclusive regimen-can lead to durable survival, the trial aims to provide evidence for a paradigm shift in the treatment of FLT3-ITD-mutated AML, potentially offering a transplant-free alternative for selected patients.
Interventions
DRUGGVA + HDAC Consolidation & Gilteritinib Maintenance
Phase I. Induction Therapy (2 cycles): Gilteritinib plus 80 mg, orally (po), once daily (qd), continuously from Day 1 of Cycle 1 until the end of Induction.Venetoclax + Azacitidine (VA Regimen): Azacitidine: 75 mg/m², intravenously (iv) or subcutaneously (sc), once daily on Days 1-7 of each 28-day cycle.Venetoclax: Cycle 1: Dose ramp-up: 100 mg po on Day 1, 200 mg po on Day 2, then 400 mg po once daily from Day 3 to Day 28.Subsequent Cycles: 400 mg po once daily on Days 1-28 of each 28-day cycle. Phase II. Consolidation Therapy (3 cycles): High-Dose Cytarabine (HiDAC): 3.0 g/m², intravenously (iv), over 3 hours, every 12 hours (q12h) on Days 1, 3, and 5 (total of 6 doses per cycle)；Gilteritinib: Dose increased to 120 mg, orally (po), once daily (qd), from day8 to day21. The interval of each cycle is 30 days. Phase III. Maintenance Therapy: Gilteritinib: 120 mg, orally (po), once daily (qd), continuously for up to 3 months.
Sponsors
First Affiliated Hospital of Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Each subject (or their legal representative) must sign an informed consent form (ICF) before any specific study procedures or tests, indicating that he/she understands the purpose and procedures of the study and is willing to participate. * Age ≥ 18 years or reaching the legal minimum adult age (whichever is greater) and ≤ 60 years (at screening); * Newly diagnosed acute myeloid leukemia with FLT3-ITD mutation according to the European LeukemiaNet (ELN) 2022 diagnostic criteria (no VAF requirement), with no low-risk or high-risk genetic features as defined by ELN 2022. * ECOG performance status ≤ 2. Biochemical indicators must be within the following limits within 21 days before randomization and at baseline: ALT and AST ≤ 3× upper limit of normal (ULN); total bilirubin ≤ 3× ULN; serum creatinine ≤ 2× ULN or CrCl ≥ 40 mL/min. LVEF determined by echocardiography is within the normal range (LVEF \> 50%).
Exclusion criteria
* Diagnosed with acute promyelocytic leukemia (APL), BCR-ABL positive acute myeloid leukemia, or AML secondary to previous chemotherapy or radiotherapy. * History of other malignancies, except for adequately treated non-malignant skin melanoma, cured in situ tumors, or other solid tumors that have been treated and have had no evidence of disease for at least 2 years. * Assessed as unfit for intensive chemotherapy based on the following criteria: ECOG performance status ≥ 2 at screening; severe cardiac diseases (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina); severe pulmonary diseases (e.g., DLCO ≤ 65% or FEV1 ≤ 65%); creatinine clearance \< 45 ml/min (calculated by Cockcroft-Gault equation), liver disease with total bilirubin \> 1.5 times the normal upper limit (ULN); any other comorbidities deemed incompatible with intensive chemotherapy by the attending physician. * Uncontrolled fungal, bacterial, or viral infections. * Known active clinically relevant liver disease (e.g., active hepatitis B or C); known history of HIV infection (participants should undergo HIV testing before randomization). * History of allergy to any excipients in gilteritinib tablets. * Pregnant or breastfeeding women. * Other conditions deemed unsuitable for this study by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission (CRc) Rate after 2 induction cycles | At day 28 of cycle 2 of GVA induction therapy (each cycle is typically 28 days with 2-weeks intervals). | CRc is defined as the proportion of participants achieving CR or CRi based on 2022 ELN criteria. CR: Bone marrow blasts \<5%, ANC ≥1.0 x 10⁹/L, platelets ≥100 x 10⁹/L, no extramedullary disease, and transfusion independence. CRi: Bone marrow blasts \<5%, no extramedullary disease, and insufficient hematologic recovery to qualify for CR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MRD Negativity Rate | At the time of CRc assessment (at day 28 of cycle 2). | The proportion of participants who achieve CRc and subsequently achieve Measurable Residual Disease (MRD) negativity, defined as \< 0.1% by multiparameter flow cytometry. |
| Deep Molecular Negativity Rate (for FLT3-ITD) | At the time point for CRc assessment (at day 28 of cycle 2) | The proportion of participants who achieve deep molecular negative, defined as \< 0.0001% (10\^-6) via the DeepScan molecular assay, to the patients who achieved CRc |
| Overall Survival (OS) | follow up 24 months | Time from enrollment to death from any cause, whichever came first (censored at last follow-up for survivors) |
| Leukemia-Free Survival (LFS) | follow up 24 months. | Time from first composed complete remission to relapse or death, whichever occurred first |
| Molecular Free Survival (mLFS) | follow up 24 months | The time from first deep molecular negative (FLT3-ITD \< 0.0001%) to molecular relapse (above the 0.0001% threshold) or death from any cause |
| Cumulative Incidence of Relapse (CIR) | follow up 24 months | The cumulative probability of morphologic relapse, considering death without relapse as a competing risk. |
| Cumulative Incidence of Molecular Relapse (mCIR) | follow up 24 months | The cumulative probability of molecular relapse, defined as the re-emergence of FLT3-ITD at or above the 0.0001% threshold, to participants who achieved deep molecular negativity, considering death without molecular relapse as a competing risk. |
Countries
China
Contacts
CONTACTJie Sun
Outcome results
None listed