Leukemia, Lymphoid, Leukemia, Myeloid, Myelodysplastic Syndromes, Myelofibrosis, Lymphoma, Malignant, Multiple Myeloma, Waldenstrom Macroglobulinemia
Conditions
Brief summary
This study is examining a chemotherapy regimen and immune suppressive medications in the setting of an allogeneic stem cell transplant. A pilot clinical trial to characterize the incidence, prevalence and function of myeloid-derived suppressor cells (MDSCs) and immune checkpoint regulators (V-domain Ig Suppressor of T-cell Activation \[VISTA\], cytotoxic T-lymphocyte- associated protein 4 \[CTLA-4\], programmed death-ligand 1 \[PD-L1\]) during early immune recovery following an allogeneic stem cell transplant. The site will use a myeloablative regimen of fludarabine with busulfan, adopted from CALGB 100801, to define clinical endpoints, including engraftment, 100 day survival and one year survival (Objective #1). The site will characterize the incidence, prevalence and function of MDSCs and immune checkpoint regulators in patients' blood and bone marrow following transplantation (Objective #2). The site will correlate these laboratory results with clinical outcomes and the incidence of graft-versus-host disease (GVHD). As an exploratory aim, in those patients experiencing GVHD and requiring treatment, the site will define the MDSCs frequency and checkpoint regulator expression and correlate these results with the patient's response to GVHD therapy.
Interventions
DRUGFludarabine
Fludarabine: 30 mg/m2 daily for 5 days
DRUGBusulfan
Busulfan: 100 mg/m2 daily for 4 days
BIOLOGICALRabbit ATG
Rabbit ATG: Related donors: 1.5 mg/kg daily x 2 days (on days -6 and -5) Unrelated donors: 1.5 mg/kg on day - 6 2 mg/kg on day -5 2.5 mg/kg on day -4
DRUGMethotrexate
Methotrexate: Related donors: 5 mg/m2 on days 1, 3 and 6 Unrelated donors: 5 mg/m2 on days 1, 3, 6 and 11
Sponsors
Dartmouth-Hitchcock Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age less than or equal to 75 years 2. The patient must be approved for transplant by the treating transplant physician. This includes completion of their pretransplant workup, as directed by standard Dartmouth-Hitchcock Medical Center (DHMC) Standard Operating Procedures (SOPs). DHMC SOP for Pretransplant Evaluation of allogeneic recipient. 3. The patient must have a disease, listed below, with treatment responsiveness that the treating transplant physician believes will benefit from an allogeneic stem cell transplant. The diseases include: 1. Acute leukemia AML (Acute Myeloid Leukemia), ALL (Acute Lymphoid Leukemia) 2. Chronic leukemia CML (Chronic Myeloid Leukemia), CLL (Chronic Lymphoid Leukemia) 3. Myelodysplasia 4. Myelofibrosis 5. Lymphoma NHL (Non-Hodgkin's Lymphoma) and Hodgkin's disease 6. Plasma cell disorder, including myeloma, Waldenstrom's Macroglobulinemia 4. Donor availability- the patient must have an identified donor 1. Sibling Availability of a 6 out of 6 identical donor 2. Unrelated donor: Availability of a 6 out of 6 unrelated donor 5. No human immunodeficiency virus (HIV) infection or active hepatitis B or C 6. Easter Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 7. Diffusing capacity of the lungs for carbon monoxide DLCO more than or equal to 40 percent predicted 8. Left ventricular ejection fraction more than or equal to 35 percent 9. Serum bilirubin less than 2x upper limit of normal transaminases less than 3x normal at the time of transplant 10. No active or uncontrollable infection 11. In female, a negative pregnancy test if experiencing menstrual periods 12. No major organ dysfunction precluding transplantation 13. No evidence of an active malignancy that would limit the patient's survival to less than 2 years. If there is any question, the principal investigator can make a decision.
Exclusion criteria
1. Psychiatric disorder or a mental deficiency of the patient that is sufficiently severe to make compliance with the treatment unlikely, and making informed consent impossible. 2. Major anticipated illness or organ failure incompatible with survival from bone marrow transplant. 3. History of refractory systemic infection Donor eligibility 1. Human leukocyte antigen (HLA) 6 out of 6 matched related or unrelated donor. 2. The donor must be healthy and must be willing to serve as a donor, based on standard guidelines 3. The donor must have no significant comorbidities that would put the donor at marked increased risk 4. There is no age restriction for the donor 5. Informed consent must be signed by donor, if sibling donor, or by third party if unrelated donor. Donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients who are surviving at 100-Days post-transplant | 100 Days | 100-Day survival of patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessing all subjects' response to treatment at 100 days post-transplant | 100 Days | Response to treatment at 100 days using standard international response criteria, based on CIBMTR definitions. |
| Assessing all subjects' response to treatment at 1 year post-transplant | 365 Days | Response to treatment at one year using standard international response criteria, based on CIBMTR definitions. |
| Assessing all subjects' survival at 1 year post-transplant | 365 Days | One year survival |
| Time to marrow engraftment | 100 Days | Time to marrow engraftment (defined as absolute neutrophil count \> 500/mm3 and platelets \> 20,000/mcl for three consecutive days (count first day as engraftment) |
| Assessing the number of treatment-related adverse events | 365 Days | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 |
| Collecting the incidents of GvHD experienced by patients post-transplant | 365 Days | Incidence of acute and chronic GVHD |
| Assessing the donor-chimerism at 30, 60 and 90 days post-transplant | 30, 60, and 90 Days | Donor-recipient chimerism following transplant at Days 30, 60 and 90. |
| Assessing the mortality rate of patients in the first 100 days post-transplant | 100 Days | Treatment-related mortality in the first 100 days |
Countries
United States
Outcome results
None listed