Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm
Conditions
Brief summary
Intensive conditioning regimens used in allogeneic hematopoietic cell transplant (HCT) help to eliminate hematologic tumors and reduce the risk of relapse, but are also characterized by high toxicity. Total marrow and lymphoid irradiation (TMLI) is a specialized radiation technique that specifically targets marrow and lymphoid tissue to maximize antitumor efficacy while reducing off target toxicity. Despite these benefits, TMLI is technically challenging and time consuming. The radiation oncology team at Stanford has developed an automated TMLI platform to overcome these challenges. In this phase II trial, automation will be incorporated into a previously validated conditioning regimen of fludarabine/cyclophosphamide/TMLI HCT with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis to confirm the feasibility and safety of automation in patients receiving allogeneic HCT for high-risk myeloid malignancies.
Interventions
RADIATIONVMAT-Based Total Marrow and Lymphoid Irradiation (TMLI)
Patients receive VMAT-based TMLI with daily image-guided radiation therapy (IGRT) for treatment localization and verification prior to radiation delivery.
DRUGFludarabine
Fludarabine 25 mg/m² IV administered daily on Days -7 through -3.
DRUGCyclophosphamide
Cyclophosphamide 14.5 mg/kg IV on Days -7 and -6 as part of conditioning and 50 mg/kg IV on Days +3 and +4 as post-transplant GVHD prophylaxis.
BIOLOGICALAllogeneic Peripheral Blood Stem Cell Transplantation (PBSCT)
Allogeneic peripheral blood stem cell transplantation administered on Day 0.
DRUGMycophenolate mofetil (MMF)
Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.
DRUGTacrolimus
Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.
Sponsors
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
for 20 Gy Arm (Cohort A) 1. Age, Performance Status, and Graft Criteria require all of the following bullet points: * Age 18 to 60 years (inclusive) * HCT Co-Morbidity score (HCT-CI) \< 5 (http://www.qxmd.com/calculate-online/hematology/hct-ci)(31) * Adequate performance status is defined as Karnofsky score ≥ 70% * Patients must be receiving an allogeneic peripheral blood stem cell graft * Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor. 2. Eligible Diseases (Any one of the following) Acute Myeloid Leukemia (AML) Must have at least one of the following characteristics: * Blasts \>5% in the peripheral blood and/or bone marrow after \>2 prior lines of AML directed therapy, present during the trial screening window * Adverse plus risk by AlloHCT Refined ELN Criteria: defined as having complex cytogenetics, TP53 mutation, or MECOM rearrangement confirmed at any time point.(32) Myelodysplastic syndrome Must have at least one of the following characteristics at the time of conditioning: * Blasts \>10% in the peripheral blood and/or bone marrow after \>1 prior line of therapy. * TP53 mutation confirmed at any time point Myeloproliferative neoplasms (MPN) or MDS/MPN overlap. Must have at least one of the following characteristics: * Blasts \>10% in the peripheral blood and/or bone marrow during the trial screening window * TP53 mutation confirmed at any time point 3. Adequate organ function is defined as all of the following: Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction \> 45% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC \> 50% predicted, and absence of O2 requirements. Liver: Transaminases \< 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation). Renal: Creatinine \< 2.0 mg/dL (adults) and creatinine clearance \> 40 mL/min. 4. Must be FIRST allogeneic HCT 5. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment. 6. Voluntary written consent Inclusion Criteria for 12 Gy Arm (Cohort B) 1. Age, Performance Status, and Graft Criteria require all of the following bullet points: Age 18 to 70 years (inclusive) Adequate performance status is defined as Karnofsky score ≥ 70% Patients must be receiving an allogeneic peripheral blood stem cell graft Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor. 2. Eligible Diseases (Any of the following) Acute Myeloid Leukemia (AML) Myelodysplastic syndrome Myeloproliferative neoplasm MDS/MPN overlap 3. Must have relapse after prior allo HCT 4. Adequate organ function is defined as all of the following: Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction \> 40% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC \> 40% predicted, and absence of O2 requirements. Liver: Transaminases \< 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation). Renal: Creatinine \< 2.0 mg/dL (adults) and creatinine clearance \> 40 mL/min. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment. 5. Voluntary written consent
Exclusion criteria
1. Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a negative pregnancy test prior to starting therapy. 2. Untreated active infection. Controlled or asymptomatic infections requiring continued antimicrobial therapy are permissible. 3. Active HIV infection, defined as HIV infection with detectable viral load 4. Active central nervous system malignancy 5. GVHD requiring systemic therapy including \> 0.25 mg/kg prednisone (or equivalent) or other systemic therapy for GVHD (e.g., tacrolimus, sirolimus, ruxolitinib, belumosodil, ibrutinib, axatilimab). 6. Any other medical or psychological condition that is deemed serious and unsafe for clinical trial participation. 7. Exposure to prior radiation that is deemed unsafe for clinical trial participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non-Relapse Mortality (NRM) | Day 100 after transplantation | Death without prior disease relapse following allogeneic peripheral blood stem cell transplantation. |
| Neutrophil Engraftment | Through Day 100 after transplantation | Neutrophil engraftment following allogeneic peripheral blood stem cell transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Relapse | Day 100 post-transplant | Disease relapse following allogeneic peripheral blood stem cell transplantation. |
| Disease-Free Survival (DFS) | Day 100 post-transplant | Disease-free survival following allogeneic peripheral blood stem cell transplantation. |
| Overall Survival (OS) | Day 100 post-transplant | Overall survival following allogeneic peripheral blood stem cell transplantation. |
| Incidence of Grade II-IV Acute Graft-versus-Host Disease (GVHD) | Day 100 post-transplant | Incidence and severity of Grade II-IV acute graft-versus-host disease following allogeneic peripheral blood stem cell transplantation. |
| Incidence of Grade III-IV Acute Graft-versus-Host Disease (GVHD) | Day 100 post-transplant | Incidence and severity of Grade III-IV acute graft-versus-host disease following allogeneic peripheral blood stem cell transplantation. |
| Bearman Regimen-Related Toxicity | Day 100 post-transplant | Regimen-related toxicity assessed using the Bearman Toxicity Scale. Toxicity will be evaluated by organ system and graded according to severity (Grades I-IV). |
Countries
United States
Contacts
CONTACTHany Elmariah
PRINCIPAL_INVESTIGATORHany Elmariah, MD
Stanford University
Outcome results
None listed