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

Phase 3

Active, not recruiting

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

Interventions: Drug: Cyclophosphamide
Drug: Fludarabine
Radiation: Total Body Irradiation
Drug: Tacrolimus
Drug: cellcept
Drug: g-csf
Procedure: Peripheral Blood Transplant

Registration Number: NCT03480360

Lead Sponsor: Dartmouth-Hitchcock Medical Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 21

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Johns Hopkins' conditioning regimen	Peripheral Blood Transplant	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	Total Body Irradiation	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	Cyclophosphamide	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	Fludarabine	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	Tacrolimus	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	cellcept	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant
Johns Hopkins' conditioning regimen	g-csf	Cyclophosphamide, fludarabine, total body irradiation, immune suppression including tacrolimus and cellcept, Granulocyte colony-stimulating factor (G-CSF), and peripheral blood transplant

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced Donor-Recipient Chimerism Following Transplant at Days 30, 60, and 90.	Days 30, 60, and 90 post-peripheral blood transplant	Define subjects who experience donor-recipient chimerism following transplant at days 30, 60 and 90. All patients were assessed for donor-recipient chimerism at days 30, 60, and 90, but only one patient experienced chimerism. Day 90 for this patient is reported.
Number of Participants Who Survived to 100-Days Post-transplant	100 days post date of peripheral blood transplant	Define 100-day survival of subjects
Number of Participants Who Survived to One Year Post-Transplant.	One year post date of peripheral blood transplant	Define one year survival of subjects
Number of Participants Who Experienced a Successful Engraftment	Post-peripheral blood transplant	Define number of subjects who experience a successful engraftment: Defined as absolute neutrophil count \> 500/mm3 and platelets \> 20,000/mcl for three consecutive days (count first day as engraftment)
Number of Participants Who Achieved a Response to Treatment at 100 Days	100 days post-peripheral blood transplant	Define response to treatment at 100 days post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria.
Number of Participants Who Achieved a Response to Treatment at One Year	One year post-peripheral blood transplant	Define response to treatment at one year post-peripheral blood transplant. The Standard International Criteria for responses for each disease will be used, based on CIBMTR (Center for International Blood and Marrow Transplant Research) criteria.
Number of Participants Who Experienced Toxicities Associated With This Treatment Regimen	Post-peripheral blood transplant	Define subjects who experienced toxicities associated with this treatment regimen
Number of Participants Who Had Incidence of Acute GVHD	Post-peripheral blood transplant	Define subjects who had incidence of acute GVHD
Number of Participants Who Had Incidence of Chronic GVHD	Post-peripheral blood transplant	Define subjects who had incidence of chronic GVHD
Number of Participants Who Experienced Treatment-Related Mortality Within the First 100 Days	100 days post-peripheral blood transplant	Define subjects who experienced treatment-related mortality within the first 100 days post-peripheral blood transplant

Secondary Outcome Measures

Name	Time	Method
Myeloid-derived Suppressor Cells (MDSCs) After Graft vs. Host Disease (GVHD) Diagnosis - Checkpoint Regulator Expression	Post-transplant through study completion or death, assessed up to 3 years post-transplant	In those patients experiencing GVHD, the study team will define the checkpoint regulator expression on MDSCs
MDSCs After GVHD Diagnosis - Frequency	Post-transplant through study completion or death, assessed up to 3 years post-transplant	In those patients experiencing GVHD, the study team will define the MDSCs frequency.
Immune Checkpoint Regulators - Incidence	Days 30, 60, and 90 post-transplant	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.
MDSCs After GVHD Diagnosis - Peripheral Blood Mononuclear Cells	Post-transplant through study completion or death, assessed up to 3 years post-transplant	In those patients experiencing GVHD, the study team will define the peripheral blood mononuclear cells and myeloid subsets.
MDSCs After GVHD Diagnosis - Myeloid Subsets Using Flow Cytometry	Post-transplant through study completion or death, assessed up to 3 years post-transplant	In those patients experiencing GVHD, the study team will define the myeloid subsets.
Immune Checkpoint Regulators - Function	Days 30, 60, and 90 post-transplant	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.
Immune Checkpoint Regulators - Prevalence	Days 30, 60, and 90 post-transplant	To characterize the prevalence of immune checkpoint regulators (VISTA, CTLA-4, PD-1) during early immune recovery following an allogeneic stem cell transplant.