Pilot Trial of Allogeneic Blood or Marrow Transplanation for Primary Immunodeficiencies

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

- Patients 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 monogenetic mutation 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 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 four arms that vary in conditioning intensity and/or mycophenolate
mofetil (MMF) duration. Patients age > 65 will only be eligible for either the
reduced-intensity conditioning (RIC or RIC-MMF) or immunosuppression-only (IOC) arms.
The IOC arm will have a standard risk and high risk cohort.

- IOC arm: pentostatin 4 mg/m(2)/day IV on days -9 and -5, low-dose cyclophosphamide
orally daily on days -9 through -2

- RIC and RIC-MMF arm: pentostatin 4 mg/m(2)/day IV on days -11 and -7, low-dose
cyclophosphamide orally daily on days -11 through -4; busulfan IV, pharmokinetically
dosed, on days -3 and -2.

- Myeloablative (MAC) arm: pentostatin 4 mg/m(2)/day IV on days -13 and -9, low-dose
cyclophosphamide orally daily on days -13 through -6; busulfan IV, pharmokinetically
dosed, on days -5, -4, -3, and -2.

- Patients will be assigned to the MAC arm if one or more of the following are present:

- Splenomegaly attributable to the underlying PID

- Evidence of a primary hematologic marrow malignancy or proliferative process,
unless myelosuppressive therapy has been given in the 3 months prior to the start
of conditioning

- PID where experience has shown that MAC is needed to fully reverse the disease
phenotype

- Patients may be assigned to the standard risk cohort of the IOC arm if one or more of
the following are present:

- DNA repair telomere maintenance defect, or familial cancer predisposition syndrome

- PID with absent or very low numbers of T-lymphocytes

- Severely hypocellular or aplastic bone marrow, without clonal abnormalities or
evidence of myelodysplastic syndrome

- In the 3 months prior to the planned start of allo BMT conditioning, receipt of
cytotoxic chemotherapy, hypomethylating agents, or targeted/immunomodulatory
therapies with antiproliferative effects on the marrow

- PID where experience has shown that minimal conditioning is necessary for
successful engraftment of both T- and myeloid lineages

- Patients may be assigned to the high risk cohort of the IOC arm if significant end-organ
dysfunction is present and it is felt that a conditioning regimen that includes busulfan
would likely be associated with intolerable, life-threatening toxicities for the
patient.

- Patients who do not meet criteria for the MAC or IOC arm will receive RIC on the RIC or
RIC-MMF arm. However, conditioning arm assignment may ultimately deviate from the above
criteria based on other patient and disease factors

- 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 +180, 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.

- Patients with DNA repair/telomere defects familial cancer syndromes may receive a
reduced dose (25mg/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 monogenetic mutation 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.

- All mutation testing will be performed on NIAID protocols (such as 07-I-0033
-Detection and Characterization of Infections and Infection Susceptibility;
PI: Steve Holland), with genetic counseling and education through these
established protocols.

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 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 MAC, 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. LVEF greater than or equal to 30% for
patients receiving IOC.

- Pulmonary function tests: DL(co) (corrected for hemoglobin) and FEV(1) greater
than or equal to 50% of predicted for the MAC arm, greater than or equal to 40%
of predicted for the RIC and RIC-MMF arms, and greater than or equal to 30%
predicted for the IOC arm; 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 USA-ITS-NIH reference.

- Bilirubin less than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or
hemolysis) for patients receiving MAC, RIC or RIC-MMF and bilirubin less than or
equal to 5.0 mg/dL for patients receiving IOC (unless due to Gilbert s syndrome
or hemolysis). ALT and AST less than or equal to 5 times ULN for patients
receiving MAC or ALT and AST less than or equal to 10 times ULN for patients
receiving RIC, RIC-MMFor IOC. Patients who are above these bilirubin, ALT, or AST
thresholds may be eligible for the RIC, RIC-MMF or IOC 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 - DONOR:

- Age greater than or equal to 4 and weight of greater than or equal to 15 kg.

- Karnofsky performance status of 90-100% (adults) or Lansky Play Performance Status of
100% (children).

- Related donors with at least a haplotype at HLA-A, B, C, DR, and DQ loci that is
shared with the recipient by high resolution typing, excluding an identical twin or
unrelated donors matched 9-10/10 at HLA-A, B, C, DR, and DQ loci by high resolution
typing

- Ability of subject or Legally Authorized Representative to understand and the
willingness to sign a written informed consent document; medically fit and willing to
donate

- Related donors for recipients who have monogenetic mutations must be unaffected. For
recipients with de novo mutations, testing of related donors is largely not required,
but is recommended in all cases and is required when the donor is the child of the
recipient. Mutation testing needs to be performed by a CLIA-certified lab, if such
testing is available. For donors who carry one mutated allele of a PID which is
inherited in either an autosomal recessive or X-linked fashion, the donor must have no
discernable symptomatology or penetrance of the mutation suggesting that they are
affected carriers. This should be verified through disease-appropriate quantitative
and functional assays to assess the function of the potential donor s immune system
(e.g. whole blood EBV DNA qPCR, NKG2D activity, TBNK panel, and quantitative
immunoglobulin levels for a female carrier of the MAGT1 mutation that causes X-linked
immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia
(XMEN)). Furthermore, the X-chromosome inactivation pattern should be assessed for
female carriers of X-linked diseases if they are considered as potential donors to
confirm favorable and complete lyonization of hematopoietic cells. For PIDs inherited
in an autosomal dominant fashion, donors who have one mutated allele for the recipient
s disease will be considered ineligible to donate, regardless of the donor s
phenotype. Additional blood tests may be required to assess for quantitative and/or
qualitative defects in the donor s immune system, particularly in cases where PID
mutation testing is not available or the PID mutation is not identified.

--A NIAID protocol (07-I-0033, Detection and Characterization of Infections and
Infection Susceptibility, PI: Steve Holland) is already in place and will handle all
the genetic/genomic analysis for recipients and potential donors on this protocol,
including the management of results, genetic counseling, and education.

- Related donors: No history of opportunistic infections, autoimmunity,
hemoglobinopathy, red cell enzymopathy, or malignancy, apart from nonmelanomatous skin
cancer or healed cervical cancer in situ.

- HIV negative, hepatitis B virus surface antigen negative, and hepatitis C virus
antibody negative.

- Related donors undergoing bone marrow harvest should be deemed fit for the operative
procedure and related donors undergoing apheresis should be deemed fit for the
collection procedure.

- Related donors will undergo the Donor Health History Screen by skilled staff in the
Blood Services Section for adult donors and age-appropriate questioning when indicated
for pediatric donors to determine donor eligibility using standard DTM criteria.

EXCLUSION CRITERIA - DONOR:

- Donors must not be pregnant. Donors of childbearing potential must use an effective
method of contraception, including one or more of the following: intrauterine device,
hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy,
partner s vasectomy, barrier methods (condom, diaphragm, or cervical cap), or
abstinence from the day of signing consent through day +60 of the recipient s
allo-BMT.

- History of a psychiatric disorder which in the opinion of the PI may compromise
compliance with the transplant protocol, or which does not allow for appropriate
informed consent.

- Other medical constraints that in the opinion of the PI constitute exclusion.

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/.