Haploidentical Allogeneic Peripheral Blood Transplantation: Examining Checkpoint Immune Regulators' Expression

Study Overview
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Brief Summary
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The standard Johns Hopkins' regimen will be used in study subjects, with the use of donor peripheral blood stem cells, rather than marrow. Clinical outcomes will be defined while focusing efforts on immune reconstitution focusing on immune checkpoint regulators after a related haploidentical stem cell transplant.

Detailed Description
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We propose a clinical trial to define clinical endpoints, including engraftment, 100-day survival and one year survival (Objective #1). We will characterize the incidence, prevalence and function of immune checkpoint regulators in patients' blood and bone marrow following transplantation (Objective #2). We will correlate these laboratory results with clinical outcomes and the incidence of GVHD. As an exploratory aim, in those patients experiencing GVHD and requiring treatment, we will define the frequency/expression of checkpoint regulator expression and correlate these results with the patient's response to GVHD therapy.

Official Title
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Haploidentical Allogeneic Peripheral Blood Transplantation: Clinical Trial and Laboratory Correlates Examining Checkpoint Immune Regulators' Expression

Conditions
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Acute Myeloid Leukemia, Chronic Lymphocytic Leukemia, Chronic Myeloid Leukemia, Myelodysplasia, Myeloproliferative Disorder, Myelofibrosis, Lymphoma, Lymphoma, Non-Hodgkin, Plasma Cell Disorder

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Radiation: Total Body Irradiation
* Drug: Tacrolimus
* Drug: cellcept
* Drug: g-csf
* Procedure: Peripheral Blood Transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: less than 75 years The patient must be approved for transplant by the treating transplant physician. This includes completion of their pre-transplant workup, as directed by standard Dartmouth-Hitchcock Medical Center (DHMC) Standard Operating Procedure (SOP) (DHMC SOP - Pre-transplant Evaluation of allogeneic recipient (Appendix). 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 - Acute Myeloid Leukemia, Acute Lymphocytic Leukemia Chronic leukemia - Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia Myelodysplasia Myeloproliferative disorder Myelofibrosis Lymphoma - Non-Hodgkin's Lymphoma or Hodgkin's disease Plasma cell disorder, including myeloma, Waldenstrom's Macroglobulinemia Donor availability- the patient must have an identified RELATED haplo-identical donor No Human Immunodeficiency Virus infection or active hepatitis B or C Eastern Cooperative Oncology Group performance status: 0-2 Diffusing capacity of carbon monoxide (DLCO) greater than or equal to 40 % predicted Left ventricular ejection fraction greater than or equal to 40% Serum bilirubin < 2x upper limit of normal; transaminases < 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 PI 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) haplo-identical matched related. The donor must be healthy and must be willing to serve as a donor, based on standard National Marrow Donor Program (NMDP) guidelines and DHMC SOP - Donor Evaluation (Appendix) The donor must have no significant co-morbidities that would put the donor at marked increased risk There is no age restriction for the donor Informed consent must be signed by donor DONOR EXCLUSION CRITERIA The NMDP guidelines for exclusion criteria will be used (Appendix). In addition, the following donors are NOT eligible: Pregnant or lactating donor HIV or active Hep B or C in the donor Donor unfit to receive G-CSF 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
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Johns Hopkins' conditioning regimen<br>Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant | Drug: Cyclophosphamide<br>* 14.5 mg/kg for 2 days (days -6, -5) and then 50 mg/kg for two days (days 3, 4)<br>Drug: Fludarabine<br>* 30 mg/m2 daily for 5 days<br>Radiation: Total Body Irradiation<br>* 200 centigray (cGy) for one day (day -1)<br>Drug: Tacrolimus<br>* 1 mg IV daily, (or the oral equivalent) adjusted to achieve a level between 5 and 15 ng/ml. If there is no evidence of GVHD, discontinue Tacrolimus by Day 180.<br>Drug: cellcept<br>* dose at 15 mg/kg po three times per day (maximum dose of 3 grams/day). Stop Cellcept at Day 35 following transplantation.<br>Drug: g-csf<br>* 5 mcg/kg/d starting day 5 and continue until Absolute Neutrophil Count (ANC) > 1000/mcL for 3 days.<br>Procedure: Peripheral Blood Transplant<br>* cell dose goal: < 5 x 106 Hematopoietic progenitor cell antigen CD34+ cells/kg recipient weight<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 100-Day Survival | Define 100-day survival of subjects | 100 days post date of peripheral blood transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Checkpoint Regulators - Incidence | To characterize the incidence of immune checkpoint regulators (V-domain Ig Suppressor of T-cell Activation, cytotoxic T-lymphocyte-associated protein 4 [CTLA], Programmed cell death protein 1 [PD-1]) during early immune recovery following an allogeneic stem cell transplant. | Days 30, 60, and 90 post-transplant | 
| Myeloid-derived suppressor cells (MDSCs) after Graft vs. Host Disease (GVHD) diagnosis - checkpoint regulator expression | In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs | Post-transplant through study completion or death, assessed up to 3 years post-transplant | 
| MDSCs after GVHD diagnosis - peripheral blood mononuclear cells | In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets. | Post-transplant through study completion or death, assessed up to 3 years post-transplant | 
| MDSCs after GVHD diagnosis - myeloid subsets using flow cytometry | In those patients experiencing GVHD, the study team will define the myeloid subsets. | Post-transplant through study completion or death, assessed up to 3 years post-transplant | 
| MDSCs after GVHD diagnosis - frequency | In those patients experiencing GVHD, the study team will define the MDSCs frequency. | Post-transplant through study completion or death, assessed up to 3 years post-transplant | 
| Immune Checkpoint Regulators - Prevalence | To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant. | Days 30, 60, and 90 post-transplant | 
| Immune Checkpoint Regulators - Function | Flow cytometry will be used to characterize the function of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant. | Days 30, 60, and 90 post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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haploidentical, transplant, peripheral blood, allogeneic