HMA-Venetoclax Induction in Newly Diagnosed AML (VENTURE-AML)
HMA-Venetoclax Induction in Young, Fit Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Prospective, Single-Arm, Phase II Study
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.
연구 개요
상태
상세 설명
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.
Critically, achievement of remission and MRD negativity with AZA-VEN does not preclude subsequent allogeneic HSCT - the only proven curative modality for intermediate and high-risk AML - and several retrospective series confirm successful bridging to transplant following HMA-VEN induction with outcomes comparable to intensive chemotherapy-induced remissions. This trial is therefore designed as a complete treatment platform: AZA-VEN induction followed by risk-adapted post-remission therapy.
LMIC Context and Justification Pakistan is classified as a lower-middle-income country (World Bank). The majority of AML patients are treated at public sector tertiary hospitals where intensive chemotherapy-related early mortality rates range from 15-25% due to infection, organ toxicity, and limited intensive care capacity. Cost analysis of induction chemotherapy in LMIC settings demonstrates that HMA-VEN, while associated with a higher drug acquisition cost, may produce comparable or superior total expenditure profiles when hospitalisation, transfusion, antifungal therapy, and ICU costs are incorporated. Additionally, the oral formulation of venetoclax and the subcutaneous route of azacitidine administration simplify logistics and reduce infusion-related infrastructure requirements.
A critical ethical consideration is equitable access to curative-intent therapy. If HMA-VEN can achieve remission rates non-inferior to 7+3 in the young fit population with a more tolerable toxicity profile, it represents an important advance for patients in LMIC settings who may not survive intensive induction-associated aplasia. This study is therefore not simply a replication of Western data; it addresses an unmet need specific to the Pakistani and broader South Asian patient population.
Summary of Key Supporting Evidence Study Population Regimen CR/CRi Key Findings DiNardo et al. (VIALE-A, NEJM 2020) ND AML ≥75 yr or unfit AZA+VEN 66.4% OS benefit; pivotal registration trial Wei et al. (Lancet Oncol 2020) ND AML unfit LDAC+VEN 48% Randomised; VEN+LDAC superior to LDAC alone DiNardo et al. (Blood 2021) Retrospective, young AML AZA+VEN 64-72% Bridging to HSCT feasible; MRD neg in ~40% Lachowiez et al. (JCO 2022) ND AML fit ≤60 yr Intensive+VEN ~75% Phase Ib/II; enhanced depth of remission Maiti et al. (Blood Adv 2023) Retrospective young fit HMA+VEN 68% HSCT conversion 60%; OS comparable to 7+3 NUMS-AFBMTC Registry (2022) Institutional AML cohort, Pakistan 7+3 52% Early mortality 18%; anthracycline access limited
연구 유형
등록 (추정된)
단계
- 2 단계
연락처 및 위치
연구 연락처
- 이름: Maryam Khan, MBBS, MRCP(UK),FCPS (Cl Haem)
- 전화번호: +923366395758
- 이메일: maryam.khan9882@gmail.com
연구 연락처 백업
- 이름: Kashaf ad Duja Awais, MBBS, MD
- 전화번호: +923326722200
- 이메일: kashafaddujaawais@yahoo.com
연구 장소
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Rawalpindi, 파키스탄, 46000
- National University of Medical Sciences, Clinical Trial Unit
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부수사관:
- Raheel Iftikhar, MBBS,FCPS(Med),FCPS(Cl Haem)
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부수사관:
- Aamir Aslam Awan, MBBS,FCPS(Paeds)
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연락하다:
- Maryam Khan, MBBS,MRCP,FCPS(Cl Haem)
- 전화번호: +923366395758
- 이메일: maryam.khan9882@gmail.com
-
수석 연구원:
- Maryam Khan, MBBS, MRCP (UK), FCPS(Cl Haem)
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부수사관:
- Kashaf ad Duja Awais, MBBS, MD
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참여기준
자격 기준
공부할 수 있는 나이
- 성인
건강한 자원 봉사자를 받아들입니다
설명
Inclusion Criteria
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 Exclusion Criteria
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
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
|---|---|
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다른: 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 |
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 |
연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Remission rate after Aza-Ven Therapy
기간: At the end of each cycle from Day 28-35 of Cycle (duration of each cycle is 28 days)
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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).
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At the end of each cycle from Day 28-35 of Cycle (duration of each cycle is 28 days)
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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EFS, OS, MRD, HSCT conversion rate
기간: 12-24 months
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Day 28-35 of Cycle 1 (and after Cycle 2 for non-responders).
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12-24 months
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기타 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
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Mutation association
기간: 12-24 months
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• 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
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12-24 months
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공동 작업자 및 조사자
수사관
- 연구 의자: Raheel Iftikhar, MBBS,FCPS(Med),FCPS(Cl Haem), National University of Medical Sciences
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- AFBMTC-AML-VEN-2026
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
IPD 공유 기간
IPD 공유 액세스 기준
IPD 공유 지원 정보 유형
- 연구_프로토콜
- 수액
- ICF
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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