Clinical trial NCT06111612: Intensive Conditioning withTHI/Bu/Flu/Ara-C in Allo-HSCT for Myeloid Malignancies With Extramedullary Involvement
Official title: Intensive Conditioning Regimen With Thiotepa Combined With Busulfan, Fludarabine and Cytarabine for Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Myeloid Malignancies With Extramedullary Involvement
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Acute Myeloid Leukemia
Myelodysplastic Neoplasm
Chronic Myelomonocytic Leukemia
Myeloid Sarcoma
Extramedullary Myeloid Tumor
Lead sponsor: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Sponsor class: OTHER
First posted: 2023-11-01
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Outpatient and inpatient patients

Brief summary: This study is a multicenter, single-arm, prospective phase II clinical trial that evaluates the efficacy and safety of an intensive conditioning regimen with thiotepa combined with busulfan, fludarabine, and cytarabine for allogeneic hematopoietic stem cell transplantation in the treatment of myeloid malignancies with extramedullary involvement. The conditioning regimen includes thiotepa at a dose of 5mg/kg/d from d -9 to d -8 (2 days), fludarabine at 30mg/m2/d from d -7 to d -3 (5 days), cytarabine at 1-1.5g/m2/d from d -7 to d -3 (5 days), and busulfan at 3.2mg/kg/d from d -5 to d -3 (3 days). Conditioning begins on day -9, and donor hematopoietic stem cell infusion is performed on day 0. All patients will undergo bone marrow examination on day 14 and day 28 post-transplant, followed by bone marrow examinations every 30 days within the first year after transplantation, and every 60 days within the second year after transplantation. If disease relapse is suspected during the follow-up period, bone marrow or extramedullary relapse site examinations will be conducted at any time. The primary study endpoints are the 1-year and 2-year progression-free survival (PFS) rates post-transplant. Secondary study endpoints include the incidence of acute graft-versus-host disease (GVHD) within 180 days post-transplant, cumulative relapse rates at 1 year and 2 years post-transplant, 1-year and 2-year overall survival (OS), graft-versus-host disease-free, relapse-free survival (GRFS), non-relapse mortality (NRM), cumulative incidence of chronic GVHD, and the incidence of Cytomegalovirus （CMV）and Epstein-Barr virus（EBV）reactivation within 1 year.


Eligibility criteria: Inclusion Criteria:

1. Age between 18 and less than 55 years, regardless of gender.
2. Criteria for myeloid tumors with extramedullary involvement:

   1. AML (Acute Myeloid Leukemia) with at least one extramedullary lesion achieving hematological remission (CR1 or CR2) after induction therapy.
   2. MDS (Myelodysplastic Syndrome) with at least one extramedullary lesion and bone marrow blast percentage ≥ 5% achieving hematological CR after treatment; CMML (Chronic Myelomonocytic Leukemia) with at least one extramedullary lesion (diagnosed according to WHO standards) achieving hematological CR after treatment.
   3. Control and remission of extramedullary lesions, including those in the central nervous system, testes, skin, and other extramedullary tissues.
   4. Granulocytic sarcoma with or without bone marrow involvement, and achieving remission after treatment.
3. Patients must have a suitable hematopoietic stem cell donor:

   1. Related donors must have at least 5/10 matches for HLA-A, -B, -C, -DQB1, and - DRB1.
   2. Unrelated donors must have at least 8/10 matches for HLA-A, -B, -C, -DQB1, and

      * DRB1.
4. Hematopoietic cell transplantation comorbidity index (HCT-CI) score ≤ 2.
5. ECOG (Eastern Cooperative Oncology Group) performance status: 0-2.
6. Adequate liver, kidney, and cardiopulmonary function, meeting the following requirements:

   1. Serum creatinine ≤ 1.5x ULN (the upper limit of normal).
   2. Cardiac function: Ejection fraction ≥ 50%.
   3. Baseline oxygen saturation \> 92%.
   4. Total bilirubin ≤ 1.5 x ULN; ALT and AST ≤ 2.0 x ULN.
   5. Pulmonary function: DLCO (corrected for hemoglobin) ≥ 40% and FEV1 (Forced Expiratory Volume in 1 second) ≥ 50%.
7. Patients must have the ability to understand and be willing to participate in this study and sign an informed consent form.

Exclusion Criteria:

1. History of malignancies other than myeloid tumors within the 5 years prior to screening, except for adequately treated in situ cervical cancer, basal cell carcinoma, squamous cell carcinoma of the skin, and curatively treated localized prostate cancer or ductal carcinoma in situ.
2. ECOG \> 2.
3. HCT-CI score ≥ 3.
4. Any unstable systemic diseases, including but not limited to unstable angina, recent cerebrovascular accidents or transient ischemic attacks within the 3 months prior to screening, myocardial infarction within the 3 months prior to screening, congestive heart failure (New York Heart Association \[NYHA\] class ≥ III), severe arrhythmias requiring drug treatment after pacemaker implantation, significant liver, kidney, or metabolic diseases, and pulmonary arterial hypertension.
5. Active, uncontrolled infections, including those associated with hemodynamic instability, new or worsening infection symptoms or signs, new infectious lesions on imaging, or persistent unexplained fever without signs or symptoms of infection.
6. Conditions requiring treatment such as grade 2 or higher seizures, paralysis, aphasia, recent severe cerebral infarction, severe traumatic brain injury, dementia, Parkinson's disease, or schizophrenia.
7. HIV-infected individuals.
8. Active hepatitis B (HBV) or active hepatitis C (HCV) requiring antiviral therapy.

   Patients at risk of HBV reactivation, are defined as those who are positive for hepatitis B surface antigen or core antibody without receiving antiviral therapy.
9. Pregnant or breastfeeding women.
10. Fertile males and females unwilling to use contraception during the treatment period and for 12 months after treatment.

Primary outcomes:
measure: 1y and 2y-PFS
timeFrame: 2023-2027
Secondary outcomes:
measure: aGVHD
timeFrame: 2023-2025
measure: 1y and 2y-CIR
timeFrame: 2023-2027
measure: 1y and 2y-OS
timeFrame: 2023-2027
measure: GRFS
timeFrame: 2023-2027
measure: NRM
timeFrame: 2023-2027
measure: cGVHD
timeFrame: 2023-2027
measure: CMV and EBV reactivation
timeFrame: 2023-2026
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai General Hospital
state: Shanghai
Study officials:
affiliation: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
name: Xianmin Song, MD
role: PRINCIPAL_INVESTIGATOR
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