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

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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid; Multiple Myeloma; Lymphoma, Malignant; Myelofibrosis; Waldenstrom Macroglobulinemia; Leukemia, Lymphoid
• Intervention / Treatment: Drug: Fludarabine; Drug: Busulfan; Biological: Rabbit ATG; Drug: Methotrexate

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Exclusion Criteria

6. The National Marrow Donor Program (NMDP) guidelines for exclusion criteria will be used. In addition, the following donors are NOT eligible:
7. Syngeneic donor
8. Pregnant or lactating donor
9. Human immunodeficiency virus (HIV) or active HepB or C in the donor
10. Donor unfit to receive Granulocyte-colony stimulating factor (GCSF) and undergo apheresis
11. A donor with a psychiatric disorder or mental deficiency that makes compliance with the procedure unlikely and informed consent impossible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Conditioning Regimen; Fludarabine, Busulfan, Rabbit ATG, Methotrexate

Drug: Fludarabine; Fludarabine: 30 mg/m2 daily for 5 days; Drug: Busulfan; Busulfan: 100 mg/m2 daily for 4 days; Biological: Rabbit 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; Drug: Methotrexate; Methotrexate: Related donors: 5 mg/m2 on days 1, 3 and 6 Unrelated donors: 5 mg/m2 on days 1, 3, 6 and 11

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

Collaborators and Investigators

• Sponsor: Dartmouth-Hitchcock Medical Center
• Investigators: Principal Investigator: Kenneth Meehan, MD, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2016
• Primary Completion (Actual): June 7, 2019
• Study Completion (Actual): February 11, 2022

Study Registration Dates

• First Submitted: August 15, 2016
• First Submitted That Met QC Criteria: September 26, 2016
• First Posted (Estimated): September 28, 2016

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 17, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Lymphoma; Myelodysplastic Syndromes; Multiple Myeloma; Leukemia; Leukemia, Myeloid; Waldenstrom Macroglobulinemia; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Fludarabine; Methotrexate; Busulfan; Thymoglobulin
• Other Study ID Numbers: D16127

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No