RecruitingNot ApplicableNCT07500753

A Single-arm, Prospective Study of a Cladribine-Bridged LABU Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory MDS/AML in Elderly Patients

A Single-arm, Prospective Study of a Cladribine-Bridged Lisaftolax and Busulfan Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Myelodysplastic Syndromes and Acute Myeloid Leukemia in Elderly Patients

Sponsor

The First Affiliated Hospital of Soochow University

Enrollment

30 participants

Start Date

Apr 1, 2026

Study Type

INTERVENTIONAL

Conditions

Relapsed or Refractory Acute Myeloid Leukemia (AML)MDS (Myelodysplastic Syndrome)

Summary

Acute myeloid leukemia (AML) is one of the most common hematologic malignancies. With increasing life expectancy and the aging of society, the incidence of AML in the elderly population is rising. The prognosis of elderly AML patients is significantly worse than that of younger patients: the 5-year overall survival rate in patients over 60 years is less than 20%, while the median survival in patients over 80 years is only 3-6 months (1). Improving the overall prognosis of elderly AML has become a hot topic in current hematology research. Hematopoietic stem cell transplantation (HSCT) is a therapeutic approach that involves intravenous infusion of hematopoietic stem cells with the goal of restoring bone marrow and immune function. Although several studies have focused on allo-HSCT in elderly patients, factors affecting transplant outcomes remain controversial, influencing clinical decision-making. Julian et al. retrospectively analyzed 103 elderly patients with relapsed/refractory AML who underwent allogeneic transplantation, showing that high-dose melphalan sequential chemotherapy was effective and well tolerated in elderly AML patients, with a 3-year overall survival rate exceeding 40%; disease prognosis was closely related to donor source and pre-transplant leukemic burden \[2\]. Furthermore, studies on haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in elderly patients are limited. A retrospective analysis from Peking University People's Hospital involving 199 elderly AML patients (≥50 years) who underwent allo-HSCT confirmed that haplo-HSCT is feasible in elderly AML patients; however, transplantation in a refractory/active disease state was associated with poorer transplant outcomes. A study from the EBMT summarized outcomes in 360 elderly patients (≥70 years) who underwent allogeneic transplantation in a non-remission state, reporting 2-year overall survival rates of 25.9%, 43%, and 62.4% for haplo-HSCT, unrelated donor, and matched sibling donor transplants, respectively \[3\]. The challenge in treating relapsed/refractory elderly AML patients lies in improving the tolerability of conditioning regimens and reducing conditioning-related toxicity, thereby increasing the success rate of transplantation. Venetoclax (VEN), an orally administered selective small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated efficacy in randomized clinical trials across several hematologic malignancies. As monotherapy for relapsed/refractory AML, VEN shows modest efficacy while exhibiting good tolerability \[4\]. In the global phase III clinical trial of venetoclax, in newly diagnosed AML patients unfit for intensive induction chemotherapy, venetoclax combined with azacitidine demonstrated significantly superior clinical efficacy compared to azacitidine alone, with a response rate (CR+CRi) more than three times higher than that of the control group, enabling patients to achieve faster and deeper remissions \[5\]. Our center has also accumulated extensive experience with venetoclax in post-transplant maintenance therapy for AML and in the treatment of relapsed/refractory AML \[6-7\]. Additionally, studies have confirmed the safety and efficacy of high-dose venetoclax in newly diagnosed AML \[8\]. Based on the aforementioned clinical efficacy and theoretical rationale, our center previously conducted a study investigating the venetoclax + azacitidine + busulfan (VABu) regimen in allogeneic HSCT for elderly AML patients, confirming that this novel regimen reduces conditioning-related chemotherapy toxicity, improves tolerability, and demonstrates advantages in decreasing cardiotoxicity, mucositis, infections, and organ dysfunction. Lisaftolax, as a second-generation BCL-2 inhibitor, can partially overcome venetoclax resistance and improve patient outcomes. Nevertheless, a consensus on the comprehensive systemic treatment strategy for elderly AML patients has not yet been reached globally. For high-risk or relapsed/refractory elderly AML patients, after risk stratification and assessment of response to chemotherapy, those who are suitable for allo-HSCT may receive a conditioning regimen consisting of cladribine bridged to lisaftolax and busulfan (Clad/LABu), aiming to achieve longer remission duration, reduce post-transplant relapse rates, and improve long-term survival in elderly AML patients.

Eligibility

Min Age: 50 Years

Inclusion Criteria5

(1) Age ≥ 50years. (2) Meet the 2022 World Health Organization (WHO) diagnostic criteria for acute myeloid leukemia (AML),MDS, and be diagnosed with relapsed/refractory AML after treatment, fulfilling any of the following definitions: Relapsed AML: Reappearance of leukemic cells in peripheral blood, bone marrow blasts >5% (excluding other causes such as bone marrow regeneration after consolidation chemotherapy), or extramedullary infiltration of leukemic cells after achieving complete remission (CR or CRi).
Refractory AML: Newly diagnosed cases that failed to respond after 2 courses of standard therapy; patients who relapsed within 12 months after consolidation therapy following CR; patients who relapsed after 12 months but failed to respond to conventional chemotherapy; patients with 2 or more relapses; persistent extramedullary leukemia.
MDS:Myelodysplastic Neoplasms (MDS)MDS are a group of clonal hematopoietic stem cell disorders characterized by: Dysplastic hematopoiesis (abnormal development of blood cells in the bone marrow); Cytopenias (one or more lineages of blood cells are reduced in number); Increased risk of transformation to acute myeloid leukemia (AML).Key diagnostic criteria (per WHO 2022 classification): Persistent cytopenia(s) for ≥4 months (unless specific genetic abnormalities are present); Morphological dysplasia in ≥10% of cells in one or more lineages; Presence of MDS-defining genetic abnormalities (e.g., SF3B1 mutation, isolated del(5q), TP53 biallelic alteration).
(3) Cardiac, hepatic, and renal function test results within the following limits: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN);Total bilirubin ≤ 3 × ULN;Serum creatinine ≤ 2 × ULN or creatinine clearance ≥ 40 mL/min;Left ventricular ejection fraction (LVEF) measured by echocardiography or multigated acquisition (MUGA) scan within the normal range (>50%).
(4) Have a suitable allogeneic donor. (5) Expected survival ≥ 1 month. (6) Karnofsky Performance Status (KPS) ≥ 60%, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2; (7) The patient understands the study protocol and voluntarily signs the informed consent form.

Exclusion Criteria1

(1) Patients had serious adverse reactions to investigational drugs such as allergies; (2) Patients with a history of immunodeficiency, or other acquired or congenital diseases, immunodeficiency diseases, and a history of organ transplantation; (3) Patients with hypertension, ventricular arrhythmia requiring clinical intervention, acute coronary syndrome, congestive heart failure, stroke, or other grade III or higher cardiovascular events within 6 months; (4) Patients received Class II or higher surgery within 4 weeks prior to enrollment; (5) Patient has an active and difficult-to-control infection, including but not limited to active fungal, bacterial, or viral infections that require systemic treatment, such as active HIV, hepatitis B or C; (6) Patient has active central nervous system leukemia infiltration; (7) Pregnant or lactating patients; (8) Patient is currently participating in another clinical studies; (9) Other conditions where the investigator deems the patient unsuitable for inclusion.

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Interventions

PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation

Clad+LABU Conditioning Regimen :Cladribine: 6.0 mg/m² once daily for 3 days, intravenous infusion on days -14 to -12;Cytarabine (Ara-C): 1.0 g/m² once daily for 3 days, intravenous infusion on days -14 to -12;Lomustine (CCNU): 250 mg/m² once on day -11, orally;Lisaftoclax: 1200 mg once daily for 6 days, orally on days -11 to -6;Azacitidine (AZA): 75 mg/m² once daily for 5 days, subcutaneous injection on days -10 to -6. Alternatively, or Decitabine (DAC): 20 mg/m² once daily for 5 days, intravenous infusion on days -10 to -6;Busulfan: 0.8 mg/kg every 6 hours for 3 days, intravenous infusion on days -5 to -3.