HMA-Venetoclax Induction in Young, Fit Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Prospective, Single-Arm, Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Remission rate after Aza-Ven Therapy
研究概览
简要总结
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.
详细描述
Standard of Care and Its Limitations The historical standard of care for young fit AML patients has been intensive induction chemotherapy with 7+3 (cytarabine 100 mg/m² Days 1-7 plus an anthracycline for 3 days). While CR rates of 60-80% are reported in clinical trial populations, real-world outcomes in LMIC settings are considerably inferior due to delays in diagnosis, limited access to molecular testing, high early mortality from infection, and inadequate supportive care infrastructure.
In Pakistan, the availability of 7+3 induction is widespread, but its administration is associated with prolonged periods of profound aplasia (typically 3-4 weeks), requiring inpatient intensive care support, broad-spectrum antifungal prophylaxis, and transfusion dependency. The cumulative cost of induction toxicity management frequently exceeds the cost of the chemotherapy itself, making 7+3 financially prohibitive for a significant fraction of the patient population.
Furthermore, access to anthracycline formulations (particularly liposomal daunorubicin or high-dose daunorubicin) that have shown superior outcomes in selected populations remains limited in the public sector in Pakistan. These constraints collectively create a compelling rationale to evaluate alternative, potentially less toxic, induction platforms that achieve equivalent or superior remission rates.
Rationale for HMA-Venetoclax in Young Fit AML Venetoclax, a selective BCL-2 inhibitor, induces apoptosis in AML blasts by disrupting mitochondrial-mediated survival signalling. In combination with hypomethylating agents (HMAs), venetoclax has demonstrated remarkable activity in older/unfit AML patients (VIALE-A trial: CR/CRi rate 66.4% vs 28.3% for AZA alone; median OS 14.7 vs 9.6 months). Subsequent mechanistic and clinical data have raised the hypothesis that HMA-VEN may be equally or more active in younger patients harbouring specific molecular vulnerabilities - notably NPM1 mutations, IDH1/2 mutations, and other BCL-2-dependent leukaemic subtypes.
Several emerging lines of evidence support extending HMA-VEN study to young fit patients. Firstly, pre-clinical data demonstrate that BCL-2 dependence is not age-restricted and may be determined by molecular subtype rather than patient fitness. Secondly, early phase and retrospective data from academic centres suggest that young patients with AML receiving AZA-VEN achieve CR/CRi rates of 60-75%, with MRD negativity rates of 30-50% and acceptable toxicity profiles notably different from 7+3 - specifically avoiding anthracycline-related cardiotoxicity. Thirdly, a shorter duration of neutropenia per cycle (typically 10-14 days) compared to 7+3 (21-28 days) represents a clinically meaningful advantage in resource-limited settings where supportive care capacity is finite.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must satisfy ALL of the following criteria to be eligible for enrolment:
- •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
- •Adequate end-organ function at screening (within 7 days of first study drug administration):
- •Serum creatinine ≤2 × ULN or CrCl ≥40 mL/min (CKD-EPI formula)
- •ALT and AST ≤3 × ULN (≤5 × ULN if attributed to hepatic leukaemic infiltration)
- •Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert syndrome or hepatic leukaemic infiltration)
- •LVEF ≥45% by echocardiography or MUGA (assessed within 28 days of enrolment)
- •Willing and able to provide written informed consent (patient or legally authorised representative for patients with AMS at presentation)
- •Willingness to comply with all study procedures, including bone marrow assessments, follow-up visits, and MRD monitoring
- •For women of childbearing potential (WOCBP): negative serum or urine pregnancy test within 72 hours of Cycle 1 Day 1, and agreement to use effective contraception throughout study treatment and for 12 months after last dose
- •For male patients with female partners of childbearing potential: agreement to use effective contraception and refrain from sperm donation throughout treatment and for 6 months after last dose 5.2
排除标准
- •Patients will be excluded from participation if ANY of the following apply:
- •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
- •Active, uncontrolled systemic infection at the time of enrolment that in the investigator's judgement would preclude initiation of cytotoxic therapy (note: controlled infection with appropriate antimicrobial therapy is not an exclusion)
- •Known active hepatitis B virus (HBV) infection (HBsAg positive) without established antiviral prophylaxis; or active hepatitis C virus (HCV) infection with detectable viral load
- •Known HIV infection with CD4 count <350 cells/μL or detectable viral load (HIV-positive patients with well-controlled disease on antiretroviral therapy may be enrolled after discussion with the Principal Investigator and Infectious Disease consultant)
- •Cardiac exclusions:
- •QTcF >480 ms on screening ECG
- •Clinically significant and uncontrolled arrhythmia
- •NYHA Class III-IV heart failure
- •Acute coronary syndrome or stroke within 6 months of enrolment
- •Malabsorption syndrome or other gastrointestinal condition that would significantly impair oral absorption of venetoclax
- •Concomitant strong CYP3A4 inhibitors (e.g. ketoconazole, posaconazole, voriconazole, clarithromycin) or inducers (e.g. rifampicin, phenytoin, carbamazepine) that cannot be safely discontinued or dose-adjusted. (Note: azole antifungals require venetoclax dose reduction per label - see Section 7.4)
- •Concurrent active malignancy requiring systemic therapy (patients with adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix are eligible)
- •Pregnancy or breastfeeding
- •Participation in any other interventional clinical trial within 4 weeks of enrolment
- •Any condition that, in the investigator's judgement, would compromise patient safety, protocol compliance, or the integrity of study data
研究组 & 干预措施
Aza-Ven Arm
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 r
干预措施: 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)
结局指标
主要结局
Remission rate after Aza-Ven Therapy
时间窗: At the end of each cycle from Day 28-35 of Cycle (duration of each cycle is 28 days)
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).
次要结局
- EFS, OS, MRD, HSCT conversion rate(12-24 months)