Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
Background:

 Allogeneic blood or marrow transplant is when stem cells are taken from one person s blood or
 bone marrow and given to another person. Researchers think this may help people with immune
 system problems.

 Objective:

 To see if allogeneic blood or bone marrow transplant is safe and effective in treating people
 with primary immunodeficiencies.

 Eligibility:

 Donors: Healthy people ages 4 or older

 Recipients: People ages 4-75 with a primary immunodeficiency that may be treated with
 allogeneic blood or marrow transplant

 Design:

 Participants will be screened with medical history, physical exam, and blood tests.

 Participants will have urine tests, EKG, and chest x-ray.

 Donors will have:

 Bone marrow harvest: With anesthesia, marrow is taken by a needle in the hipbone.

 OR

 Blood collection: They will have several drug injections over 5-7 days. Blood is taken by IV
 in one arm, circulates through a machine to remove stem cells, and returned by IV in the
 other arm.

 Possible vein assessment or pre-anesthesia evaluation

 Recipients will have:

 Lung test, heart tests, radiology scans, CT scans, and dental exam

 Possible tissue biopsies or lumbar puncture

 Bone marrow and a small piece of bone removed by needle in the hipbone.

 Chemotherapy 1-2 weeks before transplant day

 Donor stem cell donation through a catheter put into a vein in the chest or neck

 Several-week hospital stay. They will take medications and may need blood transfusions and
 additional procedures.

 After discharge, recipients will:

 Remain near the clinic for about 3 months. They will have weekly visits and may require
 hospital readmission.

 Have multiple follow-up visits to the clinic in the first 6 months, and less frequently for
 at least 5 years.
Background:

 -  Primary immunodeficiency diseases (PIDs) are conditions associated with major
 quantitative or qualitative immunologic abnormalities that are, in most cases, due to
 defects in cells of hematopoietic origin

 -  Participants with PID can have life-threatening complications including malignancy,
 recurrent infection, and autoimmunity/immune dysregulation

 -  Allogeneic blood or marrow transplantation (allo BMT) has the potential to cure the
 immune defect in PID and thereby reduce the morbidity and mortality associated with
 these diseases

 Objectives:

 -To estimate the acute graft-versus-host disease (aGVHD)-free, graft failure-free survival at
 day +180 after allo BMT, analyzed separately by conditioning arm/cohort

 Eligibility:

 -  Patients age greater than or equal to 4 through 75 years

 -  PID deemed to be of sufficient past severity to warrant allo BMT, by meeting the two
 criteria below:

 -  PID as defined by identified genetic defect or, in the absence of a mutation,
 patients with an immune defect potentially amenable to allo BMT who meet the
 clinical history criteria below may be eligible

 -  Clinical history of at least two of the following:

 -  Life-threatening, organ-threatening, or severely disfiguring infection

 -  Protracted or recurrent infections

 -  Infection with an opportunistic organism

 -  Chronic elevation in the blood of a latent virus

 -  Evidence of immune dysregulation

 -  Hypogammaglobulinemia/dysglobulinemia

 -  Hematologic malignancy or lymphoproliferative disorder

 -  Virus-associated solid tumor malignancy or pre-cancerous lesion

 -  At least one 7-8/8 (9-10/10) HLA-matched related or unrelated donor, or an
 HLA-haploidentical related donor

 -  Adequate end-organ function

 -  Consensus opinion by the investigative team that the patient has the potential to
 benefit from transplant despite existing, non-hematopoietic organ dysfunction

 -  Not pregnant or breastfeeding

 -  HIV negative

 -  Disease status: patients with malignancy should be referred in remission for evaluation,
 except in the case of virus-associated malignancy who may be referred at any time

 Design:

 -  The study will have two arms that vary in mycophenolate mofetil (MMF) duration.

 -  RIC and RIC-MMF arms: pentostatin 4 mg/m2/day IV on days -11 and -7, low-dose
 cyclophosphamide orally daily on days -11 through -4; busulfan IV, pharmacokinetically
 dosed, on days -3 and -2.

 -  Bone marrow is the preferred graft source. Peripheral blood stem cells are permitted

 -  GVHD prophylaxis:

 -  High-dose, post-transplantation cyclophosphamide (PTCy) on days +3 and +4,
 sirolimus on days +5 through +90, and mycophenolate mofetil (MMF) on days +5
 through +35 for all arms except the RIC-MMF arm. The RIC-MMF arm will receive MMF
 of varying durations based on a duration de-escalation schema.

 -  Participants with DNA repair/telomere defects/familial cancer syndromes may receive
 a reduced dose (25 mg/kg/day) PTCy on days +3 and +4, in addition to sirolimus and
 MMF.
-  INCLUSION CRITERIA - RECIPIENT:

 -  Patients age greater than or equal to 4 through 75 years

 -  PID deemed to be of sufficient past severity to warrant allo BMT, by meeting the two
 criteria below:

 1. PID as defined by identified genetic defect or, in the absence of a
 PID-associated genetic mutation, patients with an immune defect potentially
 amenable to allo BMT who meet the clinical history criteria below may be eligible
 upon discussion with the PI

 -  Mutations should be confirmed in a CLIA-certified laboratory, if such
 testing is available.

 -  Patients without a mutation must be deemed eligible and appropriate for allo
 BMT by the PI. Some patients may meet the clinical history criteria listed
 below, but will not be eligible if it is thought that their clinical history
 is due to a condition apart from an immune defect. In addition, patients
 with a PID of mild severity, such as those with selective IgA deficiency,
 may meet at least two of the clinical history criteria, but may be deemed
 inappropriate for allo BMT by the PI if it is felt that the risks of the
 procedure outweigh the severity of the disease.

 2. Clinical history of at least two of the following:

 -  Life-threatening, organ-threatening, or severely disfiguring infection

 -  Protracted or recurrent infections requiring unusually long or repeated
 courses of antibiotics

 -  Infection with an opportunistic organism

 -  Chronic elevation in the blood (greater than or equal to 2 documented
 elevations over a period of 6 months or longer) of a latent virus (EBV, CMV,
 HHV6, HHV8, etc.)

 -  Evidence of immune dysregulation, as manifested by autoimmune disease,
 atopy, hemophagocytic lymphohistiocytosis/macrophage activation syndrome,
 granulomas, splenomegaly, or lymphadenopathy

 -  Patients with hemophagocytic lymphohistiocytosis or macrophage activation
 syndrome related to an underlying lymphoma with no other clinical history
 suggestive of a primary immunodeficiency will not be eligible

 -  Hypogammaglobulinemia, dysglobulinemia, or impaired response to vaccination

 -  Hematologic malignancy or lymphoproliferative disorder

 -  Tissue diagnosis should be confirmed by NCI Department of Pathology, if
 prior biopsies are available

 -  Virus-associated solid tumor malignancy or pre-cancerous lesion

 -  Tissue diagnosis should be confirmed by NCI Departmentof Pathology, if prior
 biopsies are available

 -  Availability of at least one 7-8/8 (9-10/10) HLA-matched related (excluding an
 identical twin) or unrelated donor, or an HLA-haploidentical related donor

 -  Consensus among the PI, key AIs, and consultants (as necessary) that correction of the
 patient s immune system through BMT has the potential to improve the patient s health,
 quality of life, and/or life expectancy, after taking into consideration the patient s
 existing non-hematopoietic, potentially irreversible organ dysfunction

 -  Adequate end-organ function, as measured by:

 -  Left ventricular ejection fraction (LVEF) greater than or equal to 40% by 2D
 echocardiogram (ECHO) or MUGA, or left ventricular shortening fraction greater
 than or equal to 20% by ECHO for patients receiving RIC or RIC-MMF, or LVEF
 greater than or equal to 30% if the patient has radiologic evidence of aortic,
 renal, or coronary artery vasculitis.

 -  Pulmonary function tests: DL(co) (corrected for hemoglobin) and FEV(1) greater
 than or equal to 40% of predicted for the RIC and RIC-MMF arms; or in pediatric
 patients, if unable to perform pulmonary function tests, there should be no
 evidence of dyspnea at rest, no requirement for supplemental oxygen, and oxygen
 saturation >92% on room air. Calculations will be based on the values reported in
 CRIS.

 -  Bilirubin less than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or
 hemolysis) for patients receiving RIC or RIC-MMF; ALT and AST less than or equal
 to 10 times ULN for patients receiving RIC or RIC-MMF. Patients who are above
 these bilirubin, ALT, or AST thresholds may be eligible for the RIC or RIC-MMF
 arms if evaluated by a hepatologist who deems the liver function test
 abnormalities to be potentially reversible with bone marrow transplant.

 -  Estimated creatinine clearance of greater than or equal to 40 mL/min/1.73 m(2),
 calculated using the Cockcroft-Gault equation for adults and Schwartz formula for
 pediatric patients, for patients with creatinine levels above the institutional
 upper limit of normal

 -  Adequate central venous access potential

 -  Karnofsky or Lansky performance status of greater than or equal to 60% or ECOG
 performance status of 2 or less

 -  Ability of subject to understand and the willingness to sign a written informed
 consent document

 -  Not pregnant or breastfeeding. As therapeutic agents used in this trial may be harmful
 to a fetus, women of childbearing potential and men must agree to use adequate
 contraception (hormonal or barrier method of birth control; abstinence) prior to study
 entry and for at least one year post-allo BMT. Should a woman become pregnant or
 suspect she is pregnant while she or her partner is participating in the study, she
 should inform her treating physician immediately.

 -  Disease status: Patients with malignancy are to be referred in remission for
 evaluation, except in cases of virus-associated malignancy who may be referred at any
 time. Should a patient have progressive disease or a donor becomes unavailable after
 enrollment, the patient will be referred back to his/her primary
 hematologist-oncologist for treatment. If this course of action is not in the best
 interest of the patient according to the clinical judgment of the PI, then the patient
 may receive standard treatment for the malignant disease under the current study,
 although this should only occur as a bridge to transplant. If under either of these
 settings, it becomes apparent that the patient will not be able to proceed to
 transplant, then he/she must come off the study. Patients receiving standard therapy
 will be told about the therapy, associated risks, potential benefits, alternatives to
 the proposed therapy, and the availability of receiving the same treatment elsewhere,
 outside of a research protocol.

 EXCLUSION CRITERIA - RECIPIENT:

 -  Patients who are receiving any other investigational agents, with the exception of
 virus-specific cytotoxic T-cells for the treatment of viral infection/reactivation
 prior to allo BMT.

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to agents (cyclophosphamide, busulfan, pentostatin, sirolimus, MMF, G-CSF)
 used in the study

 -  Active psychiatric disorder which may compromise compliance with the transplant
 protocol, or which does not allow for appropriate informed consent

 -  Active central nervous system (CNS) involvement by malignancy, except in cases of
 virus-associated malignancies with CNS involvement in which case the patient may
 benefit from the transplant to control the malignancy.

 -  MAGT1 mutation and active need to take anti-platelet agents and/or therapeutic
 anti-coagulation that cannot be interrupted during aplasia.

 -  HIV positive or other acquired immunodeficiency that, as determined by the PI,
 interferes with the assessment of PID severity and/or the attribution of clinical
 manifestations of immunodeficiency to a PID.

 Inclusion Criteria (Related Donor):

 -Related donor deemed suitable and eligible and willing to donate per clinical evalations
 who are additionally willing to donate blood, urine, and marrow specimens for research.
 Related donors will be evaluated in accordance with existing Standard Policies and
 Procedures for determination of eligibility and suitability for clinical donation. Note
 that participation in this study is offered to all related donors but is not required for
 clinical donation, so it is possible that not all related donors will enroll on this study.

 Exclusion Criteria (Related Donor):

 None

 INCLUSION CRITERIA - UNRELATED DONOR:

 -Unrelated donors will be evaluated in accordance with existing NMDP Standard Policies and
 Procedures, available at:
 http://bethematch.org/About-Us/Global-transplant-network/Standards/, except for the
 additional requirement of EBV serostatus testing. Note that participation in this study is
 offered to all unrelated donors but not required for clinical donation, so it is possible
 that not all unrelated donors will enroll on this study.

 EXCLUSION CRITERIA - UNRELATED DONOR:

 -Unrelated donors: failure to qualify as a National Marrow Donor Program (NMDP) donor per
 current NMDP Standards, available at:
 http://bethematch.org/About-Us/Global-transplant-network/Standards/.