This phase II trial studies the safety of a donor hematopoietic stem cell transplant and combination chemotherapy and to see how well they work as an initial treatment given after cancer has not responded to other treatments (salvage therapy) in treating patients with acute myeloid leukemia that did not respond to treatment (refractory) with high-dose cytarabine-based chemotherapy that was given as the first treatment (induction therapy). Drugs used in chemotherapy, such as decitabine, clofarabine, idarubicin, cytarabine, venetoclax, busulfan, fludarabine, and anti-thymocyte globulin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving chemotherapy and total-body irradiation before a donor peripheral blood or bone marrow stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient’s immune cells and help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving tacrolimus, mycophenolate mofetil, cyclophosphamide, and methotrexate after the transplant may stop this from happening. Giving a donor hematopoietic stem cell transplant together with combination chemotherapy may be a better treatment for acute myeloid leukemia.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02441803.
PRIMARY OBJECTIVES:
I. To determine the safety and feasibility of allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage treatment for patients with primary induction failure (PIF) acute myeloid leukemia (AML).
II. To determine efficacy of AHSCT following decitabine, clofarabine, idarubicin, cytarabine (DCIA) and venetoclax salvage chemotherapy evaluated by overall response rate (RR), defined as complete response (CR) or CR without platelet recovery (CRp) or CR with insufficient hematological recovery (CRi).
SECONDARY OBJECTIVES:
I. To determine the percentage of patients with PIF AML eligible for AHSCT after up to 2 courses of induction chemotherapy.
II. To determine the early treatment-related mortality (TRM) (within first 4 weeks of first salvage chemotherapy regimen with DCIA and day 100 TRM after AHSCT.
III. To determine the efficacy DCIA regimen as salvage chemotherapy for patients with PIF AML (% of patients who achieve =< 5% bone marrow blasts prior to AHSCT).
IV. To determine the TRM at 1 year, relapse rate (RR), overall survival (OS) and event-free survival (EFS) for patients with PIF AML treated with DCIA followed by early AHSCT.
OUTLINE:
DCIA SALVAGE CHEMOTHERAPY: Patients receive decitabine intravenously (IV) over 1 hour on days 1-5; clofarabine IV over 1 hour on days 6-9; idarubicin IV over 30 minutes on days 6-8; cytarabine IV over 2 hours on days 6-10; and venetoclax orally (PO) once daily (QD) on days 1-14 or PO QD on days 1-4.
CONDITIONING REGIMEN: Beginning 21 days after completion of DCIA salvage chemotherapy, all eligible patients receive busulfan IV over 3 hours, fludarabine IV over 1 hour, and clofarabine IV over 1 hour on days -6 to -3. Patients receiving stem cells from a matched unrelated donor also receive anti-thymocyte globulin IV over 4 hours on days -3 and -2. Patients receiving stem cells from a haploidentical donor also undergo total body irradiation (TBI) on day -2.
TRANSPLANT: Patients undergo bone marrow or peripheral blood AHSCT on day 0.
GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receiving stem cells from a haploidentical donor receive tacrolimus IV for 2 weeks and then orally (PO) for at least 4 months after the transplant and mycophenolate mofetil IV or PO three times daily (TID) beginning on day 5 and continuing until at least day 100. Patients also receive cyclophosphamide IV over 3 hours on days 3 and 4. Patients receiving stem cells from a matched sibling or matched unrelated donor receive tacrolimus per departmental guidelines and methotrexate IV over 30 minutes on days 1, 3, 6, and 11.
After completion of study treatment, patients are followed up every 3 months up to 2 years.
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorStefan Octavian Ciurea
