Ruxolitinib-Decitabine Intensified Conditioning Regimen for AML: A Randomized Trial

Official title

Ruxolitinib and Decitabine-Enhanced Conditioning Versus Modified Bu/Cy or BuF Conditioning for the Impact on Relapse of Acute Myeloid Leukemia in First Complete Remission (CR1)After Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter, Prospective Randomized Controlled Trial

Overview

This study aims to determine whether the recurrence rate of high-risk acute myeloid leukemia CR1 patients who received allogeneic hematopoietic stem cell transplantation with the Ruxolitinib, Decitabine combined with Bu/Cy or BuF intensive pretreatment regimen is reduced compared with the traditional Bu/Cy or BuFpretreatment regimen.

Detailed description

Allogeneic hematopoietic stem cell transplantation is the only radical treatment for high-risk acute myeloid leukemia (AML), but the traditional Bu/Cy pretreatment regimen is highly toxic and has a high recurrence rate after transplantation (the long-term survival rate is only 10-30%). Although the existing improved regimens such as sequential chemotherapy can reduce the leukemia burden, they lead to prolonged myelosuppression time (17-39 days) and a non-relapse mortality rate as high as 17.2%. There is an urgent need to develop new pretreatment regimens that have both strong anti-leukemia effects and low toxicity.

Studies have found that the JAK-STAT signaling pathway is generally abnormally activated in hematological tumors such as AML. The objective response rate of Ruxolitinib (a JAK1/2 inhibitor) as a monotherapy for relapsed/refractory leukemia reached 45%. When combined with the demethylated drug decitabine, it can synergistically inhibit leukemia cells. Clinical data show that decitabine reduces the recurrence rate after transplantation by 20% (15.0% vs 38.3%), and the combination of the two has good safety. The main adverse reaction is grade 1-2 hematological toxicity.

Our center innovatively proposed the Rux-Dec-mBu/Cy or BuF combined regimen: integrating Ruxolitinib (step-based dose reduction) and decitabine (20mg/m²/d) on the basis of the classic Bu/Cy or BuF. Previous single-arm studies have shown that the one-year recurrence rate of CR1 patients is 0%, and the incidence of toxicity above grade 3 is less than 11%. This study intends to conduct a multicenter randomized controlled trial to verify the superiority of this regimen in reducing recurrence after transplantation in patients with high-risk AML CR1. Its core advantage lies in simultaneously achieving anti-leukemia enhancement (through JAK-STAT targeting and epigenetic regulation) and controllable toxicity (The median grain deficiency time was shortened to 14 days).

Interventions

• Combination product Ruxolitinib, Decitabine
  1. Decitabine: 20 mg/m²/day, administered from Day -15 to Day -10. 2. Ruxolitinib: * 10 mg twice daily (bid), Day -15 to Day -5 * 5 mg twice daily (bid), Day -4 to Day -3 * 5 mg once daily (Qd), Day -2

Primary outcome measures

• GRFS [Time frame: 1 year]

Secondary outcome measures (12)

• Cumulative recurrence rate (CIR) [Time frame: 1 years after transplantation]
• Progression-Free Survival（PFS） [Time frame: 1 years after transplantation]
• CR rate [Time frame: 30 days after transplantation]
• The incidence of aGVHD [Time frame: 100 days after transplantation]
• The incidence of cGVHD [Time frame: 1 years after transplantation]
• Disease-free survival rate (DFS) [Time frame: 1 years after transplantation]
• Treatment-related safety indicators [Time frame: 1 years after transplantation]
• Non-relapse mortality [Time frame: 1 year]
• The cumulative incidence of virus reactivation [Time frame: Day +180 days post-transplantation]
• Graft failure [Time frame: +28 days after transplantation]
• Neutrophil engraftment [Time frame: +28 days after transplantation]
• Platelet engraftment [Time frame: +28 days after transplantation]

Eligibility criteria

Inclusion criteria

• 1\) Acute myeloid leukemia with indications for allogeneic hematopoietic stem cell transplantation, CR1 2) Have HLA-matched sibling donors or haploidentical donors or ≥8/10 HLA-matched unrelated donors 3) The patients' ages range from 12 to 64 years old 4) Liver function: ALT and AST≤2.5 times the upper limit of normal values, bilirubin ≤2 times the upper limit of normal values 5) Renal function: Creatinine ≤ the upper limit of the normal value 6) There are no uncontrollable infections or serious mental and psychological disorders 7) Sign the informed consent form.

Exclusion criteria

• 1\. Patients with acute promyelocytic leukemia (M3) 2. One of the donor and recipient is pregnant 3. Suffering from mental illness or other conditions that prevent one from following the plan.

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

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Chinese PLA General Hospital — Beijing

Publications

• Xuan L, Dai M, Jiang E, Wang Y, Huang F, Fan Z, Xu N, Nie D, Liang X, Chen H, Ye J, Shi P, Liu H, Jin H, Lin R, Yan C, Zhang Y, Sun J, Han M, Liu Q. The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelod PMID 36702138
• Li Z, Shi W, Lu X, Lu H, Cao X, Tang L, Yan H, Zhong Z, You Y, Xia L, Hu Y, Wang H. Decitabine-Intensified Modified Busulfan/Cyclophosphamide Conditioning Regimen Improves Survival in Acute Myeloid Leukemia Patients Undergoing Related Donor Hematopoietic Stem Cell Transplantation: A Propensity Score Matched Analysis. Front Oncol. 2022 Mar 16;12:844937. doi: 10.3389/fonc.2022.844937. eCollection 20 PMID 35371981
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• Tang X, Valdez BC, Ma Y, Zhang Q, Qu C, Dai H, Yin J, Li Z, Xu T, Xu Y, Chen J, Zhu X, Chen Z, Wu D, Andersson BS. Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2021 Jul;56(7):1674-1682. doi: 10.1038/s41409-021-01238-5. Epub 2021 Feb 26 PMID 33637882
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Identifiers

NCT: NCT07101588 · S2024-678-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗