Haplo-identical Transplantation for Severe Aplastic Anemia, Hypo-plastic MDS and PNH Using Peripheral Blood Stem Cells and Post-transplant Cyclophosphamide for GVHD Prophylaxis
Haplo-identical Transplantation for Severe Aplastic Anemia, Hypo-plastic MDS and PNH Using Peripheral Blood Stem Cells and Post-transplant Cyclophosphamide for GVHD Prophylaxis
Background:

 Severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS), and paroxysmal nocturnal
 hemoglobinuria

 (PNH) cause serious blood problems. Stem cell transplants using bone marrow or blood plus
 chemotherapy can help. Researchers want to see if using peripheral blood stem cells (PBSCs)
 rather than bone marrow cells works too. PBSCs are easier to collect and have more cells that
 help transplants.

 Objectives:

 To see how safely and effectively SAA, MDS and PNH are treated using peripheral blood
 hematopoietic stem cells from a family member plus chemotherapy.

 Eligibility:

 Recipients ages 4-55 with SAA, MDS or PNH and their relative donors ages 4-75

 Design:

 Recipients will have:

 -  Blood, urine, heart, and lung tests

 -  Scans

 -  Bone marrow sample

 Recipients will need a caregiver for several months. They may make fertility plans and a
 power of attorney.

 Donors will have blood and tissue tests, then injections to boost stem cells for 5-7 days.

 Donors will have blood collected from a tube in an arm or leg vein. A machine will separate
 stem cells and maybe white blood cells. The rest of the blood will be returned into the other
 arm or leg.

 In the hospital for about 1 month, recipients will have:

 -  Central line inserted in the neck or chest

 -  Medicines for side effects

 -  Chemotherapy over 8 days and radiation 1 time

 -  Stem cell transplant over 4 hours

 Up to 6 months after transplant, recipients will stay near NIH for weekly physical exams and
 blood tests.

 At day 180, recipients will go home. They will have tests at their doctor s office and NIH
 several times over 5 years.
Severe aplastic anemia (SAA),myelodysplastic syndrome (MDS), and paroxysmal nocturnal
 hemoglobinuria (PNH) are life-threatening bone marrow disorders. For SAA patients, long term
 survival can be achieved with immunosuppressive treatment. However, of those patients treated
 with immunosuppressive therapy, one quarter to one third will not respond, and about 50% of
 responders will relapse.

 Although allogeneic stem cell transplantation (allo-SCT) offers the opportunity of cure,
 HLA-matched donors are available for only half the patients needing a transplant. Combined
 haplo-cord transplantation has recently been shown to be a viable transplant option for those
 patients lacking an HLA matched donor. In our ongoing protocol 08-H-0046, we have utilized
 this approach in 29 patients with SAA, and SAA evolving to MDS with 27/29 patients having
 sustained engraftment and achieving transfusion independence. However, engraftment patterns
 have varied substantially and, in some patients,, cord engraftment was profoundly delayed or
 never occurred.

 Haploidentical peripheral blood stem cell transplantation (haplo-SCT) has the advantage over
 cord transplantation of immediate allograft availability, higher stem cell doses, and the
 feasibility of repeating cell collections if necessary for collecting CD34+ cells for stem
 cells boosts or lymphocytes to treat or prevent disease relapse or infection. Recently, the
 use of post-transplant cyclophosphamide (Cy) has been shown to be an effective strategy to
 prevent GVHD in recipients of haploidentical HSCT, but most reports have focused on patients
 with hematological malignancies. At present, few data exist on the use of haploidentical
 transplantation using post-transplant cyclophosphamide for patients with aplastic anemia that
 have ATG-refractory disease and are heavily-transfused and HLA-alloimmunized. These patients
 are at an exceedingly high-risk for graft rejection compared to other patient populations.

 This research protocol is therefore designed to evaluate the safety and effectiveness of
 using an unmanipulated GCSF mobilized peripheral stem cell allograft from a haploidentical
 donor and post-transplant cyclophosphamide for patients with SAA,SAA evolving to MDS, or PNH
 that has proven to be refractory to conventional therapy in patients who lack an HLA-matched
 donor (sibling/ or matched unrelated donor) and who do not have access to a good quality
 umbilical cord product that meets criteria for expansion (due to insufficient numbers of TNC
 and/or CD 34+ cells and/or inadequate HLA match) on NHLBI protocol number # 17-H-0091.

 The primary endpoint of the study is chronic GVHD-free survival (defined as the percentage of
 patients who are alive with no evidence of moderate or severe chronic GVHD at 1-year
 post-transplant). Secondary endpoints will include engraftment, 100 day and 200-day treatment
 related mortality (TRM), and standard transplant outcome variables such as non-hematologic
 toxicity, incidence and severity of acute and chronic GVHD, and relapse of disease. Health
 related quality of life will also be assessed as secondary outcome measure.
-  INCLUSION CRITERIA - RECIPIENT:

 -  Diagnosed with severe aplastic anemia with bone marrow cellularity <30% (excluding
 lymphocytes) associated with RBC or platelet transfusion dependence and/or neutropenia
 (absolute neutrophil count less than or equal to 1000 cells/ microL or for patients
 receiving granulocyte transfusions, absolute neutrophil count less than or equal to
 1000 cells/ uL before beginning granulocyte transfusions).

 OR

 --History of severe aplastic anemia transformed to MDS. that meet the following criteria:
 a) International Prognostic Scoring System (IPSS) risk category of INT-1 or greater, b) <5%
 myeloblasts and <30% of cellularity in the bone marrow on screening morphologic analysis.

 OR

 --PNH that is either refractory to treatment with eculizumab/ravulizumab or occurs in
 patients who don t have access to treatment with eculizumab associated with either a) life-
 threatening thrombosis and/or b) cytopenia associated with transfusion dependence and/or c)
 recurrent and debilitating hemolytic crisis.

 -  Subjects with severe aplastic anemia, hypoplastic MDS or PNH with associated bone
 marrow failure syndromes who have intolerance of or failure to respond to standard
 immunosuppressive therapy.

 -  Availability of at least one HLA- haploidentical (i.e. > 5/10 and less than or equal
 to 8/10 HLA match) related donor (HLAA,

 B, C, DR, and DQ loci) who is available to donate stem cell graft (6-75 years old).

 -  The patient does not have any HLA antibodies detectable against any of the mismatched
 HLA alleles expressed by the haplo-donor.

 -  Ages 4-55 years inclusive.

 -  Ability to comprehend the investigational nature of the study and provide informed
 consent. The procedure will be explained to subjects aged 4-17 years with formal
 consent being obtained from parents or legal guardian.

 EXCLUSION CRITERIA - RECIPIENT (ANY OF THE FOLLOWING):

 -  Availability of an HLA identical or 9/10 HLA matched (HLA A, B, C, DR, and DQ loci)
 -relative to serve as a stem cell donor.

 -  The patient is deemed to be a candidate for a 10/10 HLA matched unrelated stem cell
 transplant (availability of a donor and resources required for such a transplant).

 -  The patient is eligible for transplantation using an ex vivo expanded cord blood unit
 on NHLBI protocol 17-H-0091

 -  ECOG performance status of 2 or more.

 -  Major anticipated illness or organ failure incompatible with survival from transplant.

 -  Current pregnancy, or unwillingness to take oral contraceptives or use a barrier
 method of birth control or practice abstinence to refrain from pregnancy, if of
 childbearing potential for one year.

 -  HIV positive.

 -  Diagnosis of Fanconi s anemia (by chromosome breakage study).

 -  Diffusion capacity of carbon monoxide (DLCO) <40% using DLCO corrected for Hgb or lung
 volumes (patients under the age of 10 may be excluded from this criterion if they have
 difficulty performing the test correctly and thus are unable to have their DLCO
 assessed).

 -  Left ventricular ejection fraction <40% (evaluated by ECHO)

 -  Transaminases > 5x upper limit of normal.

 -  Direct bilirubin >3 mg/dl.

 -  Creatinine clearance < 50 cc/min/BSAm2 by 24-hour urine collection adjusted by body
 surface area.

 -  Serum creatinine > 2.5 mg/dl

 -  Presence of an active infection not adequately responding to appropriate therapy.

 -  History of a malignant disease liable to relapse or progress within 5 years.

 INCLUSION CRITERIA - DONOR:

 Donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are
 additionally willing to donate blood for research. Donors will be evaluated in accordance
 with existing Standard NIH Policies and Procedures for determination of eligibility and
 suitability for clinical donation. Note that participation in this study is offered to all
 donors, but is not required for a donor to make a stem cell donation, so it is possible
 that not all donors will enroll onto this study.

 EXCLUSION CRITERIA - RELATED DONOR:

 None