Ruxolitinib and Decitabine for High Risk Hematological Malignancies

Overview

The purpose of this study is to determine the efficacy and safety of Ruxolitinib and Decitabine intensified Conditioning Regimen in Patients with High Risk hematological malignancies undergoing allogeneic peripheral blood stem cell transplantation.

Full Title of Study: “Ruxolitinib and Decitabine Intensified Conditioning Regimen for Patients With High Risk Hematological Malignancies Underwenting Allogeneic Stem Cell Transplantation”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 1, 2023

Detailed Description

Allogeneic hematopoietic stem cell transplantation should be offered to eligible patients with high risk hematological malignancies whenever feasible. To further improve the outcome of transplantation patients with high risk hematological malignancies, the investigators developed a modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine. In this study, the investigators tested the efficacy and feasibility of the modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine in Patients with high risk hematological malignancies undergoing allogeneic peripheral blood stem cell transplantation.

Interventions

  • Drug: modified By/Cy conditioning regimen intensified by Ruxolitinib and Decitabine
    • Day -15 to -14 : Decitabine 20 mg/m2/day, Ruxolitinib 70mg bid; Day-10: Cytarabine 1.6 g/m2/day CI (only for Haploidentical and unrelated donor), Ruxolitinib 60mg bid; Day- 9: Cytarabine 4g/m2/day CI, Ruxolitinib 60mg bid; Day- 8 to -7: Busulfan 0.8mg/kg Q6h iv, Ruxolitinib 50mg bid; Day-6: Busulfan 0.8mg/kg Q6h iv, Ruxolitinib 40mg bid; Day-5: Cyclophosphamide 1.8 g/m2/day CI, Ruxolitinib 30mg bid; Day-4: Cyclophosphamide 1.8 g/m2/day CI, Ruxolitinib 20mg bid; Day-3: Carmustine 250mg/m2/day iv, Ruxolitinib 10mg bid; Day-2: Ruxolitinib 5mg bid; Day-1: Ruxolitinib 5mg qd;

Arms, Groups and Cohorts

  • Experimental: Ruxolitinib combined with Decitabine
    • Ruxolitinib and Decitabine conditioning regimen All recipients in this arm received the modified Bu/Cy conditioning regimen intensified by Ruxolitinib and Decitabine. The conditioning regimen for allogeneic hematopoietic stem cell transplantation consist of ruxolitinib (35 mg bid [p.o.], days -15 to -10, diminishing to day -1), decitabine (20 mg/m2/day, days -15 to -10), cytarabine (4 g/m2/day, days -10 to -9 (for unrelated donors or haploidentical donors; and 4 g/m2/day, days -9 for sibling donors)), busulfan (0.8mg/kg, Q6h, days -8 to -6), cyclophosphamide (1.8 g/m2/day, days -5 to -4);carmustine(BCNU)(250mg/m2/day, day -3),

Clinical Trial Outcome Measures

Primary Measures

  • Number of participants relapse as assessed by NCCN (National Comprehensive Cancer Network )criteria
    • Time Frame: 365 days after transplantation
    • Defined as the proportion of participants whose underlying malignancy relapsed.

Secondary Measures

  • DFS(disease-free survival )
    • Time Frame: 365 days after transplantation
    • DFS was defined as survival with no evidence of relapse or progression.
  • TRM(treatment-related mortality )
    • Time Frame: 365 days after transplantation
    • Defined as the proportion of subjects who died due to causes other than malignancy relapse.
  • Number of participants with aGVHD as assessed by acute graft versus host disease grading criteria (refer to Glucksberg criteria)
    • Time Frame: 100 days after transplantation
    • Defined as the proportion of participants who developed acute GVHD.
  • Number of participants with cGVHD as assessed by chronic graft versus host disease grading criteria (refer to NIH criteria)
    • Time Frame: 365 days after transplantation
    • Defined as the proportion of participants who developed chronic GVHD.
  • OS(overall survival )
    • Time Frame: 365 days after transplantation
    • OS was defined as the time from transplantation to death due to any cause.
  • GRFS (GVHD free, relapse free survival)
    • Time Frame: 365 days after transplantation
    • GVHD-free, relapse-free survival (GRFS) was defined as survival with no evidence of grade III-IV acute GVHD or cGVHD requiring immunosuppressive treatment, and without disease recurrence or death from any cause during the first year after transplantation.
  • infection rate
    • Time Frame: 365 days after transplantation
    • Defined as the proportion of participants who developed all kinds of infection.

Participating in This Clinical Trial

Inclusion Criteria

1. Relapsed/refractory acute leukemia with indications for allogeneic hematopoietic stem cell transplantation; High risk acute leukemia with indications for allogeneic hematopoietic stem cell transplantation; 2. Medium to high risk myelodysplastic syndrome, myeloproliferative disease, myelodysplastic syndrome/myeloproliferative disease, Chronic myelomonocytic leukemia; 3. Have matched sibling donors, ≥8/10 HLA matched unrelated donors or haploidentical donors 4. All patients should aged 12 to 65 years; 5. Liver function: ALT and AST≤2.5 times the upper limit of normal , bilirubin≤2 times the upper limit of normal; 6. Renal function: creatinine ≤the upper limit of normal; 7. Patients without any uncontrolled infections , without organ dysfunction or without severe mental illness; 8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2; 9. Have signed informed consent. Exclusion Criteria:

1. pregnant women; 2. Patients with mental illness or other states unable to comply with the protocol; 3. AML patients with t (15;17);

Gender Eligibility: All

Minimum Age: 12 Years

Maximum Age: 65 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Chinese PLA General Hospital
  • Provider of Information About this Clinical Study
    • Principal Investigator: Daihong Liu, Director – Chinese PLA General Hospital
  • Overall Official(s)
    • Daihong Liu, Principal Investigator, Chinese PLA General Hospital
  • Overall Contact(s)
    • Daihong Liu, 86-13681171597, daihongrm@163.com

References

Karjalainen R, Pemovska T, Popa M, Liu M, Javarappa KK, Majumder MM, Yadav B, Tamborero D, Tang J, Bychkov D, Kontro M, Parsons A, Suvela M, Mayoral Safont M, Porkka K, Aittokallio T, Kallioniemi O, McCormack E, Gjertsen BT, Wennerberg K, Knowles J, Heckman CA. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML. Blood. 2017 Aug 10;130(6):789-802. doi: 10.1182/blood-2016-02-699363. Epub 2017 Jun 15.

Rampal R, Ahn J, Abdel-Wahab O, Nahas M, Wang K, Lipson D, Otto GA, Yelensky R, Hricik T, McKenney AS, Chiosis G, Chung YR, Pandey S, van den Brink MR, Armstrong SA, Dogan A, Intlekofer A, Manshouri T, Park CY, Verstovsek S, Rapaport F, Stephens PJ, Miller VA, Levine RL. Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5401-10. doi: 10.1073/pnas.1407792111. Epub 2014 Dec 2.

Delgado-Martin C, Meyer LK, Huang BJ, Shimano KA, Zinter MS, Nguyen JV, Smith GA, Taunton J, Winter SS, Roderick JR, Kelliher MA, Horton TM, Wood BL, Teachey DT, Hermiston ML. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. Leukemia. 2017 Dec;31(12):2568-2576. doi: 10.1038/leu.2017.136. Epub 2017 May 9.

Venugopal S, Bar-Natan M, Mascarenhas JO. JAKs to STATs: A tantalizing therapeutic target in acute myeloid leukemia. Blood Rev. 2020 Mar;40:100634. doi: 10.1016/j.blre.2019.100634. Epub 2019 Oct 25.

Ding YY, Stern JW, Jubelirer TF, Wertheim GB, Lin F, Chang F, Gu Z, Mullighan CG, Li Y, Harvey RC, Chen IM, Willman CL, Hunger SP, Li MM, Tasian SK. Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure. Haematologica. 2018 Sep;103(9):e427-e431. doi: 10.3324/haematol.2018.192088. Epub 2018 May 17. No abstract available.

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