HMA-Venetoclax Induction in Newly Diagnosed AML

ConditionsAML AML (Acute Myeloid Leukemia)

Trial statusNot yet recruiting

Trial phasePhase 2

Trial typeInterventional

Biological sexAll

Age18-50

SponsorPakistan Blood and Marrow Transplant (PBMT) Group

About this trial

Acute myeloid leukaemia (AML) is a clonal haematological malignancy characterised by arrested myeloid differentiation and uncontrolled proliferation of blast cells in the bone marrow and peripheral blood. It is the most common acute leukaemia in adults and carries a high disease-related mortality. Globally, the median age of diagnosis is approximately 68 years; however, a significant proportion of patients are diagnosed below the age of 50 years, constituting the 'young fit' population for whom aggressive curative-intent therapy is most appropriate.

The epidemiology of AML in South Asia and Pakistan remains incompletely characterised. Published single-centre and multi-centre data from Pakistan suggest that AML represents a major proportion of haematological malignancies presenting to tertiary centres. AFBMTC, as the largest haematology and transplant centre in Pakistan, has accumulated over 2,000 HSCT procedures since 2001 and has established the necessary infrastructure for prospective clinical research in this disease.

Cytogenetic and molecular classification of AML profoundly influences prognosis and treatment decisions. The European LeukemiaNet (ELN) 2022 risk stratification framework categorises AML into Favourable, Intermediate, and Adverse risk groups based on chromosomal abnormalities and somatic mutations including NPM1, FLT3-ITD, IDH1/2, RUNX1, ASXL1, TP53, and others. This framework underpins post-remission pathway assignment in the current protocol.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Age 18-50 years (inclusive) at the time of enrolment

Confirmed diagnosis of AML (non-APL) per WHO 2022 Classification: ≥20% blasts in bone marrow or peripheral blood, or documented leukaemia-defining cytogenetic abnormality regardless of blast count (e.g. t(8;21), inv(16), t(15;17) is excluded as APL). Diagnosis must be confirmed by bone marrow aspirate and/or biopsy with morphology, flow cytometry, and cytogenetics.

Newly diagnosed AML: no prior cytotoxic therapy for AML (excluding hydroxyurea for blast cytoreduction, which is permitted for ≤7 days prior to enrolment)

ECOG Performance Status 0-2

Disqualifiers

Acute promyelocytic leukaemia (APL) [t(15;17); PML-RARA]: patients with APL must be referred for ATRA-based therapy as per institutional standard

AML secondary to myeloproliferative neoplasm (MPN) in blast phase, where prior MPN was treated with ruxolitinib within 8 weeks of enrolment (due to drug interaction potential with venetoclax)

Prior exposure to a BCL-2 inhibitor (venetoclax, navitoclax, or other) at any time

Prior exposure to HMA therapy (azacitidine or decitabine) for a pre-existing MDS or MPN within 6 months of AML diagnosis

Trial design

Design model

Single group

Treatments tested in this trial

Azacitidine 75 mg/m² SC/IV Days 1-7 + Venetoclax 400 mg orally Days 1-28 (Cycle 1 ramp-up per institutional TLS protocol); 28-day cycles; maximum 2 induction cycles
Drug
Induction Regimen: AZA-VEN The AZA-VEN induction regimen will be administered for a maximum of 2 cycles (each 28 days). Patients achieving CR/CRi/CRh after Cycle 1 will proceed directly to post-remission therapy. Drug Dose Route Days Cycle Duration Azacitidine 75 mg/m² SC or IV infusion (30 min) Days 1-7 28 days (repeat Cycle 2 if needed) Venetoclax 400 mg/day (target; after ramp-up) Oral (once daily with food or within 30 min of eating) Days 1-28 28 days Venetoclax Ramp-Up Schedule (Cycle 1 Only) To mitigate the risk of tumour lysis syndrome (TLS), venetoclax must be dose-ramped during Cycle 1. The ramp-up is not required in subsequent cycles. Days Daily Dose TLS Risk Mitigation Day 1 100 mg Hospitalise; IV hydration; allopurinol 300 mg/day initiated ≥48h before Day 2 200 mg Continue hydration; monitor electrolytes at 4, 8, 24h post first dose Day 3 400 mg (target) Continue hydration; check electrolytes at 4h post dose Day 3 Days 4-28 400 mg Outpatient permissible if TLS risk re

Treatment groups

60 Participants

are divided into 1 treatment group

Group A: Aza-Ven ArmOther 1 intervention

Trial outcomes

Primary outcomes

Remission rate after Aza-Ven Therapy

Composite complete remission rate: proportion of patients achieving CR, CRi, or CRh as assessed by treating haematologist per ELN 2022 response criteria on bone marrow assessment at Day 28-35 of Cycle 1 (and after Cycle 2 for non-responders).

Time frame

At the end of each cycle from Day 28-35 of Cycle (duration of each cycle is 28 days)

Secondary outcomes

EFS, OS, MRD, HSCT conversion rate

Day 28-35 of Cycle 1 (and after Cycle 2 for non-responders).

Time frame

12-24 months

Other outcomes

Mutation association

• To explore the correlation between molecular subtype (NPM1, FLT3, IDH1/2, TP53, RUNX1, ASXL1, KMT2A-r) and depth and durability of response to AZA-VEN

Time frame

12-24 months

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Pakistan Blood and Marrow Transplant (PBMT) Group

Lead sponsor

Source ClinicalTrials.gov

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