RIC Allo-HSCT vs. Venetoclax-Based Consolidation in Elderly AML Patients After First CR

Official title

Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Comparison to Consolidation Therapy Based Venetoclax for Elderly Patients With Acute Myeloid Leukemia After First CR

Overview

Elderly patients with acute myeloid leukemia (AML) often face unfavorable prognostic factors such as multiple comorbidities, adverse cytogenetic profiles, and pre-existing hematological disorders. The long-term survival rate remains very low, with a 5-year survival rate of only 5% to 10%. The introduction of the BCL-2 inhibitor venetoclax (Ven) has improved the induction remission rates in elderly patients. However, the question of whether to use chemotherapy maintenance or proceed with allogeneic hematopoietic stem cell transplantation (allo-HSCT) for post-remission consolidation therapy remains unclear due to the lack of prospective controlled studies. Therefore, our center plans to conduct a prospective, open-label, two-arm, non-randomized, single-center study to further explore the optimal consolidation treatment strategy for elderly AML patients at intermediate and high risk following induction complete remission (CR).

Interventions

• Drug Venetoclax
  The consolidation therapy involves a regimen of intermediate-dose cytarabine (Ara-C) combined with Ven, specifically Ara-C at 1.0 g/m²/day for 3 days (days 1-3) and Ven at 400 mg/day for 10 to 14 days (days 1-10 to 14), with each cycle lasting 4 to 6 weeks, for a total of 3 consolidation cycles. This is followed by maintenance therapy with azacitidine (AZA) at 50 mg/m²/day for 5 days (days 1-5), with each cycle lasting 4 weeks, for a total of 6 maintenance cycles.
• Drug Allogeneic transplant
  The consolidation therapy involves allo-HSCT, with the choice of conditioning regimens typically using reduced-intensity conditioning such as the Fludarabine+Busulfan (FluBu) or Fludarabine+Melphalan (FluMel) regimens commonly used by centers, which can also include Ven. FluBu regimen: Flu 30 mg/m²/day from day -10 to day -5, Bu 3.2 mg/kg/day from day -6 to day -5 or day -7 to day -5, antithymocyte globulin (ATG) (e.g., rabbit ATG at a total dose of 6-7.5 mg/kg, administered from day -4 to day

Primary outcome measures

• Relapse-free survival [Time frame: Up to 2 years]

Secondary outcome measures (3)

• Non-Relapsed Mortality [Time frame: Up to 2 years]
• Overall Survival [Time frame: Up to 2 years]
• 2-years Relapse Rate [Time frame: Up to 2 years]

Eligibility criteria

Inclusion criteria

• Diagnosed with AML according to the 2022 WHO diagnostic criteria;
• Age 60-75 years;
• Intermediate to high-risk AML according to the ELN criteria, AML with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML), or core-binding factor AML (CBF-AML) with D816 KIT mutation; or newly diagnosed hypercellular leukemia (WBC ≥ 10×10\^9/L);
• Achieved CR or CR with incomplete hematologic recovery (CRi) after one to two courses of induction chemotherapy;
• Have a matched related, haploidentical, or mismatched unrelated hematopoietic stem cell donor;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; Creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula);
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× the upper limit of normal (ULN), and total bilirubin ≤ 2× ULN;
• Echocardiography (ECHO) showing left ventricular ejection fraction (LVEF) ≥ 50%; Expected survival > 8 weeks;
• Voluntarily signed the informed consent form and can understand and comply with the study's requirements.

Exclusion criteria

• Currently has clinically active cardiovascular disease, such as uncontrolled arrhythmias, uncontrolled hypertension, congestive heart failure, any class 3 or 4 heart disease according to the New York Heart Association (NYHA) functional classification, or a history of myocardial infarction within 3 months before screening;
• Other severe diseases that may limit the patient's participation in this trial (e.g., severe infection, renal failure);
• Known human immunodeficiency virus (HIV) infection or severe viral hepatitis not controlled by medication;
• Pregnant or breastfeeding women;
• Unable to understand, comply with the study protocol, or unable to sign the informed consent form.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Zhejiang University School of Medicine — Hangzhou

Publications

• DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 1 PMID 32786187
• Kadia TM, Reville PK, Wang X, Rausch CR, Borthakur G, Pemmaraju N, Daver NG, DiNardo CD, Sasaki K, Issa GC, Ohanian M, Montalban-Bravo G, Short NJ, Jain N, Ferrajoli A, Bhalla KN, Jabbour E, Takahashi K, Malla R, Quagliato K, Kanagal-Shamanna R, Popat UR, Andreeff M, Garcia-Manero G, Konopleva MY, Ravandi F, Kantarjian HM. Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine A PMID 35704787
• Chua CC, Roberts AW, Reynolds J, Fong CY, Ting SB, Salmon JM, MacRaild S, Ivey A, Tiong IS, Fleming S, Brown FC, Loo S, Majewski IJ, Bohlander SK, Wei AH. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy. J Clin Oncol. 2020 Oct 20;38(30):3506-3517. doi: 10.1200/JCO.20.00572. Ep PMID 32687450
• Wang H, Yao Y, Mao L, Lou Y, Ren Y, Ye X, Yang M, Ma L, Zhang Y, Zhou Y, Wu J, Huang X, Wang Y, Xu H, Tong H, Zhu HH, Jin J. Venetoclax plus '2 + 5' modified intensive chemotherapy with daunorubicin and cytarabine in fit elderly patients with untreated de novo acute myeloid leukaemia: a single-centre retrospective analysis. Br J Haematol. 2023 May;201(3):568-572. doi: 10.1111/bjh.18709. Epub 2023 PMID 36863709
• Garcia JS, Kim HT, Murdock HM, Cutler CS, Brock J, Gooptu M, Ho VT, Koreth J, Nikiforow S, Romee R, Shapiro R, Loschi F, Ryan J, Fell G, Karp HQ, Lucas F, Kim AS, Potter D, Mashaka T, Stone RM, DeAngelo DJ, Letai A, Lindsley RC, Soiffer RJ, Antin JH. Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active. Blood Adv. 2021 Dec 28;5(24):5536-5 PMID 34614506

Identifiers

NCT: NCT06571825 · TROPHY-AML03

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗