Chemotherapy CLAGE-Ven Sequential With Reduced Intensity Conditioning for Refractory Acute Myelodi Leukemia

Study Overview
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Brief Summary
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The investigators developed a protocol combining chemotherapy of cladribine, cytarabine and etoposide (CLAGE) as debulking treatment sequential with reduced intensity conditioning regimen Flu-Bu to treat patients with refractory acute myeloid leukemia (AML). In this study, the aim is to further evaluate the efficacy and feasibility of the protocol with modifications: 1) reduced dose of CLAGE; 2) Reduced intensity conditioning (RIC) regimen as fludarabine, busulfan and melphalan (MBF) or total marrow irradiation (TMI); 3) Venetoclax was added to the chemotherapy and conditioning regimen.

Detailed Description
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Refractory AML is associated with poor prognosis. Allogeneic stem cell transplantation is considered as the only curative therapy. Unfortunately, conventional transplantation protocol usually has high relapse rate and high nor-relapse mortality. In previous studies, the investigators established a protocol using intensive chemotherapy (cladribine, cytarabine and etoposide) to reduced the leukemia burden followed by reduced intensity conditioning regimen of Flu-Bu3 with 7 day interval. All patients received maintenance therapy. The 1-year relapse rate was less than 20% but toxicity such as lethal infection was documented in sizable part of patients. In this study, the aim is to further evaluate the efficacy and feasibility of the protocol with following modifications: 1) dose of cytarabine and etoposide are reduced to 1g/m2 and 100mg/m2 daily; 2) conditioning regimen is based on Flu-Bu2 combined with addition of melphalan (100mg/m2) or total marrow irradiation (TMI) in case of contra-indication for busulfan or melphalan; 3) Venetoclax is added to the chemotherapy and conditioning regimen. The modifications intend to reduce both the toxicities and relapse, which may turn into a benefit of disease-free survival (DFS). This is designed as a phase II multi-center prospective study to evaluate the feasibility and efficacy of the protocol.

Official Title
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A Phase II Single Arm Study of Cladribine, Cytarabine, Etoposide and Venetoclax Sequential With Reduced Dose Conditioning of Fludarabine, Busulfan and Melphalan or Total Marrow Radiation for Refractory Acute Myeloid Leukemia

Conditions
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Refractory Leukemia

Intervention / Treatment
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* Drug: CALGE-VEN- RIC-conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with refractory AML: no remission after 2 induction therapy, relapsed AML within 6 months of 1st CR, relapse AML fail to having CR after reinduction therapy, multiple relapse and refractory relapse AML patients with >5% bone marrow blast by morphology or by LAIP flowcytometry at enrollment patients with HLA-matched sibling donor, 9-10/10 matched unrelated donor or haplo-identical family donor patients without active infection informed consent provided Exclusion Criteria: patients with abnormal liver function (enzyme >2N or bilirubin >2N) patients with abnormal renal function (Scr >1.5N) patients with poor cardiac function （EF<45%）

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CLAGE-VEN-RIC-Conditioning<br>Cladribine: 5mg/m2 day -21 to d -17 cytarabine: 1g/m2 day -21- to d -17 etoposide: 100mg/m2 day -17 to -15 venetoclax: 100mg day-21; 200mg day -20, 400mg day -19 to day-3 Fludarabine: 30mg/m2 day -7 to -3 Busulfan: 3.2mg/kg day -6 to -5 Melphalan: 50mg/m2 day -4 to -3. or Fludarabine 30mg/m2 day -7 to -3 Total marrow irradiation day-5 to -3 PBSC: day 0 Conditioning regimen cane delayed to in patients with ongoing active infection or work-up of donors after CLAGE-VEN chemotherapy based on clinicians' decision. Patients receiving all-HSCT in cytopenia are classified as sequential while patients with recovered CBC are considered as bridging transplantation. | Drug: CALGE-VEN- RIC-conditioning<br>* Intensive chemotherapy Cladribine-cytarabine-etoposide -venetoclax sequential with fludarabine, busulfan and melphalan or fludarabine and total marrow irradiation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease-free survival (DFS) | patients remain alive in remission without disease progression or relapse | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete remission (CR) | patients achieve clinical remission after transplantation | day 60 | 
| Overall survival (OS) | patients remain alive | 2 year | 
| non-relapse mortality (NRM) | patients died without evidence of disease | day 100 | 
| non-relapse mortality | patients died without evidence of disease | 2 year | 
| relapse | patients fail to achieve remission or had disease relapse | 2 year | 
| GRFS | patients remain alive without relapse, without grade III-IV aGVHD and moderate to severe cGVHD | 2 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory AML, allogeneic stem cell transplantation