Myeloid-Derived Suppressor Cells and Checkpoint Immune Regulators' Expression in Allogeneic SCT Using FluBuATG

Study Overview
=================
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.

Official Title
-----------------
A Pilot Trial Examining Myeloid-Derived Suppressor Cells and Checkpoint Immune Regulators' Expression in Allogeneic Stem Cell Transplant Recipients Using Myeloablative Busulfan and Fludarabine

Conditions
-----------------
Leukemia, Lymphoid, Leukemia, Myeloid, Myelodysplastic Syndromes, Myelofibrosis, Lymphoma, Malignant, Multiple Myeloma, Waldenstrom Macroglobulinemia

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Busulfan
* Biological: Rabbit ATG
* Drug: Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age less than or equal to 75 years 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. 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: Acute leukemia AML (Acute Myeloid Leukemia), ALL (Acute Lymphoid Leukemia) Chronic leukemia CML (Chronic Myeloid Leukemia), CLL (Chronic Lymphoid Leukemia) Myelodysplasia Myelofibrosis Lymphoma NHL (Non-Hodgkin's Lymphoma) and Hodgkin's disease Plasma cell disorder, including myeloma, Waldenstrom's Macroglobulinemia Donor availability- the patient must have an identified donor Sibling Availability of a 6 out of 6 identical donor Unrelated donor: Availability of a 6 out of 6 unrelated donor No human immunodeficiency virus (HIV) infection or active hepatitis B or C Easter Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 Diffusing capacity of the lungs for carbon monoxide DLCO more than or equal to 40 percent predicted Left ventricular ejection fraction more than or equal to 35 percent Serum bilirubin less than 2x upper limit of normal transaminases less than 3x normal at the time of transplant No active or uncontrollable infection In female, a negative pregnancy test if experiencing menstrual periods No major organ dysfunction precluding transplantation 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: 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. Major anticipated illness or organ failure incompatible with survival from bone marrow transplant. History of refractory systemic infection Donor eligibility Human leukocyte antigen (HLA) 6 out of 6 matched related or unrelated donor. The donor must be healthy and must be willing to serve as a donor, based on standard guidelines The donor must have no significant comorbidities that would put the donor at marked increased risk There is no age restriction for the donor Informed consent must be signed by donor, if sibling donor, or by third party if unrelated donor. Donor Exclusion Criteria The National Marrow Donor Program (NMDP) guidelines for exclusion criteria will be used. In addition, the following donors are NOT eligible: Syngeneic donor Pregnant or lactating donor Human immunodeficiency virus (HIV) or active HepB or C in the donor Donor unfit to receive Granulocyte-colony stimulating factor (GCSF) and undergo apheresis A donor with a psychiatric disorder or mental deficiency that makes compliance with the procedure unlikely and informed consent impossible

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Conditioning Regimen<br>Fludarabine, Busulfan, Rabbit ATG, Methotrexate | Drug: Fludarabine<br>* Fludarabine: 30 mg/m2 daily for 5 days<br>Drug: Busulfan<br>* Busulfan: 100 mg/m2 daily for 4 days<br>Biological: Rabbit ATG<br>* 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<br>Drug: Methotrexate<br>* Methotrexate: Related donors: 5 mg/m2 on days 1, 3 and 6 Unrelated donors: 5 mg/m2 on days 1, 3, 6 and 11<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who are surviving at 100-Days post-transplant | 100-Day survival of patients | 100 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to marrow engraftment | 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) | 100 Days | 
| Assessing all subjects' response to treatment at 100 days post-transplant | Response to treatment at 100 days using standard international response criteria, based on CIBMTR definitions. | 100 Days | 
| Assessing all subjects' response to treatment at 1 year post-transplant | Response to treatment at one year using standard international response criteria, based on CIBMTR definitions. | 365 Days | 
| Assessing all subjects' survival at 1 year post-transplant | One year survival | 365 Days | 
| Assessing the mortality rate of patients in the first 100 days post-transplant | Treatment-related mortality in the first 100 days | 100 Days | 
| Assessing the number of treatment-related adverse events | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 365 Days | 
| Collecting the incidents of GvHD experienced by patients post-transplant | Incidence of acute and chronic GVHD | 365 Days | 
| Assessing the donor-chimerism at 30, 60 and 90 days post-transplant | Donor-recipient chimerism following transplant at Days 30, 60 and 90. | 30, 60, and 90 Days |