Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML

Study Overview
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Brief Summary
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Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

Official Title
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A California Cooperative Clinical Study Comparing Allogeneic Hematopoietic Cell Transplantation Using Nonmyeloablative Host Conditioning With Total Lymphoid Irradiation and Anti-thymocyte Globulin Versus Best Standard of Care in Acute Myeloid Leukemia (AML) in First Complete Remission

Conditions
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Leukemia, Myeloid, Leukemia, Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Procedure: Allogeneic HSCT
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Cyclosporine (CSP)
* Drug: Mycophenolate mofetil (MMF)
* Radiation: Total lymphoid irradiation (TLI)
* Drug: Methylprednisolone sodium succinate
* Drug: Best standard care


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA ≥ 50 years of age and ≤ 75 years of age. De novo acute myelogenous leukemia (AML), based on FAB and WHO criteria. Intermediate or unfavorable cytogenetic abnormalities based on Southwest Oncology Group (SWOG) Cytogenetic Criteria. First morphologic complete remission (CR), or CRp (a complete remission but with low platelets) following 1 or 2 courses of induction therapy, documented no more than 8 weeks prior to the date of enrollment and confirmed at time of enrollment. Karnofsky Performance Score ≥ 60. Suitable for non-myeloablative transplantation or best treatment. Able to understand and willing to sign a written informed consent document. EXCLUSION CRITERIA AML with favorable cytogenetic features based on SWOG Cytogenetic Criteria AML, either treatment-related or MDS-related Active CNS disease as identified by positive CSF cytospin at time of enrollment. Prior or concurrent malignancies except localized non-melanoma skin malignancies or treated cervical carcinoma in situ. (EXCEPTION: Cancer treated with curative intent > 5 years previously is allowed. EXCEPTION: Low grade lymphoma is allowed as long as active treatment is not required for control of disease) Planned for allogeneic transplant using a full-dose conditioning Life expectancy < 1 year due to diseases other than malignancy Pregnant or breastfeeding. HIV-seropositive. Uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month. Symptomatic coronary artery disease or uncontrolled congestive heart failure. Left ventricular ejection fraction (LVEF) is not required to be measured, however if measured, exclusion if ejection fraction is < 30%. Requiring supplementary continuous oxygen. Diffusing capacity of the lungs for carbon monoxide (DLCO) is not required to be measured, however if it is measured, exclusion if DLCO < 35%. Fulminant liver failure Cirrhosis with evidence of portal hypertension or bridging fibrosis Alcoholic hepatitis Esophageal varices A history of bleeding esophageal varices Hepatic encephalopathy Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time Ascites related to portal hypertension Chronic viral hepatitis with total serum bilirubin > 3 mg/dL Symptomatic biliary disease

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment assignment was based on availability of an HLA-matched donor.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allo-HSCT + TLI + ATG<br>Participants achieving complete remission after consolidation therapy & who have 5 of 6 HLA-match sibling donor to provide PBSC harvest for transplant. Pre-transplant subjects receive: Total lymphoid radiation (TLI) Days -11 to -7, and Days -4 to -1 (2 fractions on day -1) Anti-thymocyte globulin (ATG) Days -11 to -7 Methylprednisolone Days -11 to -7 Cyclosporine (CSP) Days -4 to +2 5+ of 6 HLA-matched CD34+ cells on Day 0 Mycophenolate mofetil (MMF), Day 0 to Day +28 | Procedure: Allogeneic HSCT<br>* Allogeneic, 5+ of 6 HLA-matched PBSC transplant from sibling, mobilized to target of 5 x 10e6 CD34+ cells/kg and < 7 x 10e8 CD3+ cells/kg.<br>* Other names: Peripheral blood stem cell (PBSC) transplantation;Drug: Anti-thymocyte globulin (ATG)<br>* 1.5 mg/kg for 5 days by IV<br>* Other names: Anti-thymocyte globulin (rabbit) (ATG);Drug: Cyclosporine (CSP)<br>* 6.25 mg/kg twice daily oral<br>* Other names: cyclosporin;Drug: Mycophenolate mofetil (MMF)<br>* 15 mg/kg twice daily oral<br>* Other names: Cellcept;Radiation: Total lymphoid irradiation (TLI)<br>* 80 cGy/fraction radiotherapy in 10 fractions.<br>Drug: Methylprednisolone sodium succinate<br>* 1.0 mg/kg for 5 days by IV<br>* Other names: P-Care D80;|
| Active Comparator: Best Standard Care<br>Regular medical care for participants who achieve complete remission after standard consolidation therapy, but do not have a 5 of 6 HLA-match sibling donor. Treatment may consist of: Additional consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) Autologous transplantation Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning Umbilical cord blood transplantation Haploidentical transplantation | Drug: Best standard care<br>* Intervention consist of: Consolidation chemotherapy (3-4 cycles of cytarabine +/- an anthracycline agent, or other consolidation) Autologous transplantation Non-Myeloablative unrelated-donor transplant, +/- TLI and ATG conditioning Umbilical cord blood transplantation Haploidentical transplantation<br>* Other names: Regular medical care;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival defined as the time interval between the date of attaining a first complete remission (CR) and the date of death from any cause. The outcome is reported as the number of participants alive (without dispersion). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival (DFS) | Disease-free survival is defined as the time interval between the date of attaining a first complete remission (CR) and the date of relapse. Disease free survival (DFS) will compared to conventional therapy vs Non-myeloablative Host Conditioning (NMA HCT). The outcome is reported as the number of participants which never experienced disease relapse (without dispersion). | 2 years | 
| Non-relapse Mortality | Non-relapse mortality is defined as death that occurs after therapy, from any cause except a cause associated with relapse. This will be reported as the number of participants experiencing non-relapse mortality (a number without dispersion). | 2 years | 
| Relapse Rate | Relapse will be determined as ≥ 5% blast cells in the bone marrow, not secondary to regeneration after myelosuppressive therapy; OR emergence of extramedullary leukemia; OR the re-emergence of blasts in the peripheral blood. The outcome will be reported as the number and percentage of participants that meet these criteria (a number without dispersion). | 2 years | 
| Transplant-related Mortality | Transplant-related mortality will be assessed as any death occurring within 6 months post-transplant, from any cause except relapse. It will be measured at 100 day and 6 months after transplant. The outcome is expressed as at the number of participants experiencing transplant-related mortality (a number without dispersion). | 100 days and 6 months | 
| Complete Donor Hematopoietic Cell Chimerism | Complete donor hematopoietic cell chimerism was evaluated in transplant recipients. Complete donor chimerism will be assessed as the presence of > 95% donor T-cells (CD3+) in the blood. The outcome is reported as the percentage of participants that achieve complete donor chimerism, a number without dispersion. | 2 years | 
| Early Graft Loss | Early graft loss means a failure to achieve donor T-cell chimerism of > 5% at any time after transplant. The outcome is reported as the percentage of participants that experience early graft loss, a number without dispersion. | 2 years | 
| Patients Completing the Intended Therapy in Both Arms | The assessment for completion of the intended therapy (in both arms) will be reported as the percentage of participants, a number without dispersion | 2 years |