Hematopoietic Cell Transplant with Individualized Reduced Intensity Conditioning and Post-Transplant Cyclophosphamide for the Treatment of Patients with Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure

Status: active

This phase II trial tests how well hematopoietic cell transplant with individualized, reduced intensity conditioning and post-transplant cyclophosphamide works in treating patients with severe aplastic anemia and other forms of acquired bone marrow failure. Giving chemotherapy, with rituximab, rabbit anti-thymocyte globulin (ATG), cyclophosphamide, fludarabine and total-body irradiation before a hematopoietic stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Giving cyclophosphamide shortly after the transplant may stop this from happening. Giving hematopoietic cell transplant with individualized, reduced intensity conditioning and post-transplant cyclophosphamide may be effective in treating patients with severe aplastic anemia and other forms of acquired bone marrow failure.

Inclusion Criteria

Idiopathic severe aplastic anemia (SAA), characterized by one of the following: * Refractory cytopenia(s), with 1+ of the following: ** Platelets < 20,000/uL or transfusion dependent ** Absolute neutrophil count < 500/uL without hematopoietic growth factor support ** Absolute reticulocyte count < 60,000/uL AND bone marrow cellularity < 50% (with < 30% residual hematopoietic cells) * Early myelodysplastic features (bone marrow (BM) blasts < 5%), without history of myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML) pre-treatment. * Idiopathic SAA with post-HCT graft failure (blood/marrow donor chimerism < 5%) requiring a 2nd allogeneic HCT
Paroxysmal nocturnal hemoglobinuria (PNH), including aplastic anemia (AA)-PNH overlap syndrome, acquired pure red cell aplasia (aPRCA), or acquired amegakaryocytic thrombocytopenia (aAT), characterized by one of the following: * Refractory cytopenia(s), with 1+ of the following: ** Platelets < 20,000/uL or transfusion dependent ** Absolute neutrophil count < 500/uL without hematopoietic growth factor support ** Absolute reticulocyte count < 60,000/uL or red cell transfusion dependent AND bone marrow evidence of 1 to 3-lineage aplasia OR peripheral blood PNH clone >= 10% * Early myelodysplastic features (bone marrow (BM) blasts < 5%) without history of myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) pre-treatment. * Idiopathic PNH, aPRCA, or aAT with post-HCT graft failure (blood/marrow donor chimerism < 5%) requiring a 2nd allogeneic HCT
0-75 years of age at time of consent
Left ventricular ejection fraction ≥ 35% with no evidence of decompensated heart failure (within 30 days of conditioning regimen)
Diffusing lung carbon monoxide (DLCO) ≥ 30% predicted, no supplemental oxygen requirement (within 30 days of conditioning regimen)
Sexually active persons of childbearing potential or persons with partners of childbearing potential must agree to use a highly effective form of contraception during study treatment and for at least 4 months after the transplant. Nonchildbearing is defined as pre-pubertal, > 1 year post-menopausal or surgically sterilized. Examples of highly effective birth control methods include but are not limited to the following: * Using twice the normal protection of birth control (i.e., double-barrier) by using a condom AND spermicidal jelly or foam, or a diaphragm AND spermicidal jelly or foam. A spermicidal jelly or foam must be used in addition to a barrier method (e.g., condom or diaphragm). * Oral contraceptive pills * Depot or injectable birth control * Intrauterine device (IUD) * Transdermal contraceptive patch * Vaginal contraceptive ring * Contraceptive implants Note: Rhythm method or abstinence alone is not considered an adequate method of contraception
Provides voluntary written consent prior to the performance of any research related activity
DONOR SELECTION: Donor-specific anti-human leucocyte antigen (HLA) antibody testing requirement: Testing for antibodies targeting donor specific HLA antigens at HLA-A, B, C, DRB1, DQ and DP will be completed as per institutional standards
DONOR SELECTION: Donor options: Bone marrow or peripheral blood stem cells from: * Related donor: 4-8 HLA-antigen matched, mismatched, or haploidentical (matching at a minimum of one allele each of HLA-A, -B, -Cw, and -DRB1). Related bone marrow or peripheral blood stem cell donors must meet donor criteria as outlined in MT2012-14C: Procedure Guidelines for Related Hematopoietic Stem Cell Donors. * Unrelated donor: 7-8 HLA-antigen matched. Unrelated donors must meet National Marrow Donor Program (NMDP)/Center for International Blood and Marrow Transplant Research (CIBMTR) donor criteria

Exclusion Criteria

Pregnant, breastfeeding or intending to become pregnant during the study. Persons of childbearing potential must have a negative pregnancy test (serum or urine) within 7 days of the start of treatment
Uncontrolled infection
Evidence of moderate or severe portal fibrosis or cirrhosis on biopsy
Known allergy to any of the study components
Prior radiation therapy deemed excessive by radiation therapist for proposed low dose total body irradiation (TBI) exposure on this protocol
Diagnosis of an inherited bone marrow failure disorder such as Fanconi anemia, Telomere biology disorder, or Schwachman-Diamond syndrome, unless reviewed by the principal investigator and deemed appropriate for this approach (e.g. GATA2 deficiency)
Advanced myelodysplastic syndrome (MDS; bone marrow [BM] blasts > 5%) or acute myeloid leukemia
Psychiatric illness/social situations that, in the judgement of the enrolling investigator, would limit compliance with study requirements
Other illness or a medical issue that, in the judgement of the enrolling Investigator, would exclude the patient from participating in this study

PRIMARY OBJECTIVE:

I. To determine the grade 3-4 acute graft-versus host disease (GvHD), chronic GvHD-free, failure-free survival (GFFS) at 1-year post-HCT.

SECONDARY OBJECTIVES:

I. To determine the grade 3-4 acute GvHD, chronic GvHD-free, failure-free survival (GFFS) at 2 years post hematopoietic cell transplant (HCT).

II. To determine the incidence of neutrophil recovery at day 42 post HCT.

III. To determine the incidence of platelet recovery at 6 months post HCT.

IV. To determine the incidence of grade 3-4 acute GvHD at 100 days post HCT.

V. To determine the incidence of any chronic GvHD at 1 year post HCT.

VI. To determine the incidence of primary graft failure at day +42.

VII. To determine the incidence of secondary graft failure at 1 year.

VIII. To determine the incidence of non-relapse mortality at 100 days and 1 year.

IX. To determine the overall survival at 1 and 2 years.

X. To determine the incidence of pre-malignant clonal hematopoiesis recurrence at 1 and 2 years (Arm B with baseline clonal hematopoiesis only).

XI. To determine the incidence of EBV reactivation requiring pre-emptive therapy by day +180 amongst patients receiving day -14 rituximab (EBV IgG seropositive or EBV blood PCR positive).

CORRELATIVE OBJECTIVES:

I. Immune recovery at days +60, +100, 6 months, 1 and 2 years post-HCT.

II. Peripheral blood donor myeloid, lymphoid, B and NK cell chimerism at days +28, +60, +100, 6 months, 1 and 2 years post-HCT.

III. Incidence of major bacterial, viral, and fungal infections by day+180.

OUTLINE: Patients less than or equal to 25 years old with no clonal hematopoiesis are assigned to Arm A and patients greater than 25 and/or with clonal hematopoiesis are assigned to Arm B.

ARM A: Patients who are positive for current or prior Epstein-Barr virus (EBV) receive rituximab intravenously (IV) once on day -14. Patients receive rabbit anti-thymocyte globulin (ATG) over 4-6 hours once per day (QD) on days -9 to -7, cyclophosphamide IV over 2 hours QD on days -6 to -5, fludarabine IV QD on days -6 to -3 and total body irradiation once on day -1. Patients then receive hematopoietic stem cells IV on day 0. Patients receive cyclophosphamide IV over 2 hours QD on days +3 and +4. Patients undergo computed tomography (CT) during screening and echocardiography (ECHO), bone marrow biopsy and aspiration throughout the trial.

ARM B: Patients who are positive for current or prior EBV receive rituximab IV once on day -14. Patients receive rabbit ATG over 4-6 hours QD on days -9 to -7, cyclophosphamide IV over 2 hours QD on day -6 to -5, fludarabine IV QD on days -6 to -3 and total body irradiation twice on day -1. Patients then receive hematopoietic stem cells IV on day 0. Patients receive cyclophosphamide IV over 2 hours QD on days +3 and +4. Patients undergo CT during screening and ECHO, bone marrow biopsy and aspiration throughout the trial.

After completion of study treatment, patients are followed up weekly until day +100, at +101 to +179, 6 months, 1 and 2 years.

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Hematopoietic Cell Transplant with Individualized Reduced Intensity Conditioning and Post-Transplant Cyclophosphamide for the Treatment of Patients with Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure

Inclusion Criteria

Exclusion Criteria

United States

Minnesota

Minneapolis

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Hematopoietic Cell Transplant with Individualized Reduced Intensity Conditioning and Post-Transplant Cyclophosphamide for the Treatment of Patients with Severe Aplastic Anemia and Other Forms of Acquired Bone Marrow Failure

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