This phase I trial evaluates the safety and feasibility of using a reduced-intensity regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin prior to a CD4+ T-cell depleted haploidentical hematopoietic cell transplant (haploHCT) for the treatment of patients with severe aplastic anemia that does not respond to treatment (refractory) or that has come back (recurrent). Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid. It may also lower the body's immune response. Pentostatin blocks a protein needed for cell growth. Anti-thymocyte globulin is an immunosuppressive drug can destroy immune cells known as T-cells. HaploHCT transfers blood-forming stem cells from a healthy partially-matched donor to a patient. Administering a regimen of cyclophosphamide, pentostatin, and anti-thymocyte globulin before haploHCT may help make room for the new, healthy cells and may reduce the risk of graft versus host disease.
PRIMARY OBJECTIVES: I. To determine if the infusion of CD4+ T-cell-depleted hematopoietic cells from a haploidentical donor, following a non-myeloablative/ reduced-intensity preparative regimen is safe in patients with severe aplastic anemia (SAA). II. To determine the feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product, as assessed by: IIa. Ability to meet the minimum required CD34+ cell dose, and; IIb. Ability to meet the CD4+ T-cell depletion product release requirements. SECONDARY OBJECTIVES: I. To evaluate toxicities including type, frequency, severity, attribution, time course, and duration. (Safety/tolerability) II. To summarize and evaluate hematologic (neutrophil and platelet) recovery, including marrow failure. (Safety/tolerability) III. To estimate the incidence of infection and infectious disease related complications at 100 days. (Safety/tolerability) IV. To estimate the incidence of SAA related complications. (Safety/tolerability) V. To estimate the cumulative incidence of non-relapse mortality at 100-days, 1-year and 2-years post hematopoietic stem-cell transplantation (HCT). (Safety/tolerability) VI. To estimate the cumulative incidence of acute graft versus host disease (GvHD) (grades: II-IV, III-IV) at 100-days and chronic GvHD (grades: any, moderate-severe) at 6-months, 1-year and 2-years post HCT. (Safety/tolerability) VII. To estimate the overall survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) VIII. To estimate the disease-free survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) IX. To estimate the event-free survival probability at 100-days, 1-year and 2-years post HCT. (Survival/relapse) X. To estimate the cumulative incidence of disease relapse at 100-days, 1-year and 2-years post HCT. (Survival/relapse) XI. To describe response as categorized by graft failure, persistent post-immunosuppressant (IS) mixed chimerism, persistent IS-dependent mixed chimerism, complete chimerism. (Chimerism) XII. To summarize/characterize patient chimerism (percent of donor total nucleated and donor lineage specific cells) over time. (Kinetics) EXPLORATORY OBJECTIVES: I. To describe the ratio of donor to recipient de novo thymic T cells over the course of 2 years within the peripheral blood compartment. II. To describe the ratio of donor to recipient regulatory T cells and regulatory B cells over the course of 2 years within the peripheral blood and bone marrow compartments. III. To describe the tolerance status of donor and host-type T cells over the course of 2 years within the peripheral blood compartment. IV. To describe the T-cell repertoire of donor- and host-type T cells over the course of 2 years within the peripheral blood compartment. V. To describe the bone marrow niche and peripheral blood cytokine profile over time. VI. To describe bone marrow progenitor chimerism over time. OUTLINE: Patients receive cyclophosphamide orally (PO) and intravenously (IV), pentostatin IV, anti-thymocyte globulin IV and undergo CD4+ T-cell depleted haploHCT on study. Patients also undergo bone marrow aspirate, bone marrow biopsy, and collection of blood samples at screening and follow-up.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
Given IV
Undergo blood sample collection
Undergo bone marrow aspirate
Undergo bone marrow biopsy
Given PO and IV
Undergo CD4+ T-cell depleted haploHCT
Given IV
Ancillary studies
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of adverse events
Toxicity will be graded according to the National Cancer Institute's-Common Terminology Criteria for Adverse Events version 5.0. Graft versus host disease (GVHD) specific toxicities will be defined per 1994 Keystone Consensus Criteria. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study regimen and reversibility or outcome. This will include infectious disease related complications and autoimmune disease related complications. Cumulative incidence curves will be used for time to event variables with competing risks events such as acute GVHD or chronic GVHD. Point estimates and 90% confidence intervals will be used.
Time frame: From day -22 to day +100 or occurrence of unacceptable toxicity, whichever occurs first
Ability to meet CD4+ T-cell depleted product release requirements (feasibility)
The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet product release requirements. Product release requirements include the following: (1) CD34+ cells: Post-processing CD34+ cell target of 7.5-13.0 x 106 cells/kg of recipient body weight; (2) CD4+ T-cell depletion: \>= 97% of CD4+ T-cells in the the hematopoietic cell product for manufacturing; (3) Sterility (e.g. endotoxin and gram staining). Descriptive statistics will be used to characterize feasibility.
Time frame: Up to 3 years
Ability to meet minimum required cell dose (feasibility)
The feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product will be assessed by the ability to meet minimum required cell doses. This outcome will be evaluated using the following: (1) CD34+ collected (per day of apheresis); (2) CD34+ recovery: % CD34+ cells recovered from the CD34+ cell number in the product being manufactured (pre-CD4+ T cell depletion); (3) Cell dose: pooled and back up product; (4) Cell dose adequate given recipient's body weight plus the required pre-processed back-up set aside (yes/no); (5) Number (median, range) of apheresis; (6) % CD4+ T-cell depletion; (7) reason for not meeting product release requirements. Descriptive statistics will be used to characterize feasibility.
Time frame: Up to 3 years
Incidence of adverse events of grade 3 or higher
Time frame: Up to 3 years
Incidence of infection
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any.
Time frame: Up to 3 years
Time to neutrophil recovery
Time frame: From the date of CD4+ T-cell-depleted product infusion to the first of three consecutive days of absolute neutrophil count (ANC) >= 500/mm^3 and ANC >= 1000/mm^3, assessed up to 3 years
Time to platelet recovery
Time frame: Time to the first day of the first of three consecutive laboratory values when the platelet count is >= 20,000/mm^3 and 100,000/mm^3 without a platelet transfusion in the previous seven, assessed up to 3 years
Marrow failure
Defined as primary graft failure: failure to achieve a sustained neutrophil count of \>= 500/ mm\^3 in the absence of disease relapse by 28 days or secondary graft failure: a decline in the neutrophil count to less than 500/ mm\^3 after initial engraftment, which was unrelated to infection, medications, or disease relapse.
Time frame: Up to 28 days post transplant for primary graft failure or after initial engraftment for secondary graft failure, assessed up to 3 years
Cumulative incidence of non-relapse mortality (NRM)
NRM is defined as death occurring in a patient from causes other than disease relapse; relapse is a competing event. Cumulative incidence curves will be used for time to event variables with competing risks events. Point estimates and 90% confidence intervals will be used.
Time frame: From enrollment until non-disease related death or last follow up and from date of CD4+ T-cell-depleted product infusion, assessed up to 3 years
Cumulative incidence of acute GvHD (II-IV and III-IV)
Acute GvHD is graded according to the Keystone Consensus Criteria. The first day of acute GvHD onset at a certain grade will be used to calculate cumulative incidence curves; death is a competing event. Cumulative incidence curves will be used for time to event variables with competing risks events. Point estimates and 90% confidence intervals will be used.
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Time frame: From day 0 through day +100 post-transplant
Cumulative incidence of chronic GvHD (any and moderate-severe)
Chronic GvHD is graded according to the 2014 NIH Consensus Criteria. The first day of chronic GvHD onset at a certain grade will be used to calculate cumulative incidence curves; disease recurrence or death is a competing event. Cumulative incidence curves will be used for time to event variables with competing risks events. Point estimates and 90% confidence intervals will be used.
Time frame: From day +100 to +2 years post-transplant
Overall survival
Patients are considered a failure for this endpoint if they die, regardless of cause of death. Overall survival will be censored at last follow-up if patients are known to be alive. Kaplan-Meier curves will be used for time to event variables.
Time frame: Time from enrollment to death, assessed up to 3 years
Cumulative incidence of relapse
Disease relapse is defined as a decline in the neutrophil count to less than 500/ mm\^3 after initial engraftment, which was unrelated to infection, medications, or other causes. Death without disease recurrence will be a competing risk event. Time to disease recurrence will be censored at the last disease assessment of patients remain alive and free of disease recurrence.
Time frame: Time from enrollment/infusion of depleted hematopoietic product to first observation of disease relapse, assessed up to 3 years
Disease-free survival (DFS)
Patients are considered a failure for this endpoint if they relapse or die, regardless of cause of death. DFS will be censored at last follow-up if patients are alive and free of disease. Kaplan-Meier curves will be used for time to event variables.
Time frame: Time from enrollment/ infusion of CD4+ T-cell-depleted hematopoietic product to relapse, therapy for hemoglobinopathy, death from any cause, assessed up to 3 years
Event-free survival (EFS)
EFS will be censored at last follow-up if patients are free of any above-mentioned events. Kaplan-Meier curves will be used for time to event variables.
Time frame: Time from enrollment/infusion of CD4+ T-cell product to any of the following events (whichever occurs first): therapy for hemoglobinopathy, primary/secondary graft failure, acute GvHD, chronic GvHD, death from any cause, assessed up to 3 years
Chimerism
Persistent IS-dependent mixed chimerism: Between 10% and 94% donor chimerism at two years post-transplant and on IS. Complete chimerism: \>94% donor chimerism at two years post-transplant. Primary donor graft failure: Defined as \< 10 % donor chimerism by day +30 post-transplant.. Secondary donor graft failure: Defined as \< 10 % donor chimerism beyond day +30 in patients with prior documentation of \>= 10% donor cells by day +30. Failure is based on two separate measurements obtained at least 2 weeks apart. Line charts or scatterplots will be used for changes of endpoints over time such as chimerism.
Time frame: Up to 2 years
Kinetics
Will evaluate T-cells: CD3, CD4, CD8, B-cells: CD19, natural killer cells: CD56, monocytes: CD14, granulocytes: CD15, total nucleated cells. Line charts or scatterplots will be used for changes of endpoints over time.
Time frame: At 7, 15, 30, 60, 100, 180 days and 1, 1.5, and 2 years post-transplant