Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation

Background:

- Disorders of T-cell proliferation and/or dysregulation (TCP/D) can lead to T-cell
lymphoproliferative disorders, autoimmunity, infection, and aberrant immune activation
with resulting organ dysfunction, morbidity, and mortality.

- Allogeneic hematopoietic cell transplantation (HCT) has the potential to cure disorders
of TCP/D.

- Subjects with TCP/D may be at higher risk for graft rejection and/or disease relapse.

Primary Objective:

- Separately by arm: To estimate the percentage of recipients with >50% donor T cell
chimerism and graft-failure free survival at day +180 post-HCT

Eligibility:

- Age greater than or equal to 4 years

- TCP/D deemed to be of sufficient past severity to warrant HCT that meets at least one of
the criteria below:

- Identified germline T-cell activating mutation in the PI3k pathway

- Identified ADA2 deficiency (biallelic mutations in CECR1 (ADA2) and/or
phenotypically with low ADA2 level) leading to neutropenia requiring chronic GCSF
therapy or to transfusion-dependent anemia or thrombocytopenia

- T-cell infiltration of liver, spleen, lymph nodes, marrow, lungs, gut, or other
organs by T cells, as evidenced by laboratory, radiographic, and/or anatomic
pathology evaluation, resulting in organ dysfunction and/or organomegaly

- Latent herpesvirus infection in T lymphocytes

- History of or active evidence of hemophagocytic lymphohistiocytosis (HLH)

- Recurrent or prolonged fevers attributed to immune dysregulation

- T-cell population in blood and/or marrow with immunophenotype of large granular
lymphocytes (LGL), with or without clonality or lymphocytosis

- T-cell lymphoproliferative disorder in the setting of an underlying immune defect

- Immune-mediated cytopenias of one lineage requiring transfusion or GCSF support or
of 2 or 3 lineages with or without transfusion or support

- Chronic active Epstein-Barr virus (EBV)

- At least one potentially suitable 7-8/8 HLA-matched related or unrelated donor, or an
HLA-haploidentical related donor

- Adequate end-organ function

- Not pregnant or breastfeeding

- HIV negative

- Disease status: Subjects with malignancy should be referred in remission for evaluation
if possible, although the aggressive nature of many of these diseases necessitates the
potential need to enroll subjects onto study and treat with standard therapies before
proceeding to protocol therapy (HCT)

Design:

- There will be two arms that vary in conditioning intensity - an immunosuppression-only
conditioning (IOC) arm for high-risk subjects and a reduced-intensity conditioning (RIC)
arm.

- IOC arm: equine anti-thymocyte globulin (e-ATG) 40 mg/kg/day IV on days -14 and -13,
pentostatin 4 mg/m^2/day IV on days -9 and -5, low-dose cyclophosphamide orally daily on
days -9 through -2

- RIC arm: e-ATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m^2/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.

-- Subjects will be assigned to the IOC arm if there is significant end-organ
dysfunction present and it is felt that a conditioning regimen that includes busulfan
would likely be associated with intolerable or life-threatening toxicities for the
subject. Subjects will also be assigned to the IOC arm if they possess a DNA repair
defect, telomere maintenance defect, or familial cancer predisposition syndrome that
necessitates limiting chemotherapy as much as possible to prevent future cancer risk.

- Peripheral blood stem cells are the preferred graft source, although bone marrow is
permitted

- GVHD prophylaxis:

- PTCy on days +3 and +4 (50 mg/kg/day on RIC arm and 25 mg/kg/day on IOC arm),
tacrolimus on days +5 through +90, and MMF on days +5 through +25.

- INCLUSION CRITERIA - RECIPIENT:

- Age greater than or equal to 4 years

- TCP/D deemed to be of sufficient past severity to warrant HCT that meets at least one
of the criteria below:

- Identified germline T-cell activating mutation in the PI3k pathway

- Identified ADA2 deficiency (biallelic mutations in CECR1 (ADA2) and/or
phenotypically with low ADA2 level) leading to neutropenia requiring chronic GCSF
therapy or to transfusion-dependent anemia or thrombocytopenia

- T-cell infiltration of liver, spleen, lymph nodes, marrow, lungs, gut, or other
organs by T cells, as evidenced by laboratory, radiographic, and/or anatomic
pathology evaluation, resulting in organ dysfunction and/or organomegaly

- Latent herpesvirus infection in T lymphocytes

- History of or active evidence of hemophagocytic lymphohistiocytosis (HLH)

- Recurrent or prolonged fevers attributed to immune dysregulation

- T-cell population in blood and/or marrow with immunophenotype of large granular
lymphocytes (LGL), with or without clonality or lymphocytosis

- T-cell lymphoproliferative disorder in the setting of an underlying immune defect

- Immune-mediated cytopenias of one lineage requiring transfusion or GCSF support
or of 2 or 3 lineages with or without transfusion or support

- Chronic active EBV

- At least one potential 7-8/8 HLA-matched related (excluding an identical twin) or
unrelated donor (at HLA-A, -B, -C, and -DR), or an HLA-haploidentical related donor,
based on initial low resolution unrelated donor search and/or at least one
biologically- related family member who has at least a 25% chance of being at minimum
an HLA- haploidentical match and is potentially suitable to donate based on reported
family history. HLA typing of potential donors and/or mutation testing does not need
to be completed for eligibility.

- Adequate end-organ function, as measured by:

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

- Pulmonary function tests: DLco (corrected for hemoglobin) and FEV1 greater than
or equal to 40% of predicted for the RIC arm, and greater than or equal to 30%
predicted for the IOC arm; or in pediatric subjects, 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 greater than or equal to 3.0 mg/dL (unless due to Gilbert s syndrome or
hemolysis) for subjects receiving RIC and bilirubin greater than or equal to 5.0
mg/dL for subjects receiving IOC (unless due to Gilbert s syndrome or hemolysis);
ALT and AST greater than or equal to 5 x ULN for subjects receiving RIC or
greater than or equal to 10 x ULN for subjects receiving IOC. Subjects who are
above these bilirubin, ALT, or AST thresholds may be eligible for the RIC or IOC
arm if evaluated by a hepatologist who deems the liver function test
abnormalities to be potentially reversible with HCT.

- Estimated creatinine clearance of greater than or equal to 50 mL/min/1.73 m^2,
calculated using eGRF in the clinical lab for adults and the Schwartz formula for
pediatric subjects, if eGFR not reported by the clinical lab.

- Adequate central venous access potential

- Karnofsky (adults) or Lansky (children) performance status of greater than or equal to
50% or ECOG performance status of 2 or less for the RIC arm and greater than or equal
to 30% or ECOG performance status of 3 or less for the IOC arm

- Ability of subject or parent/legal guardian 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 HCT. 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: Subjects with lymphoproliferative disorder (LPD), LGL, HLH, or other
TCP/D disorders requiring standard therapies to prepare for HCT should be referred in
remission if possible. However, these diseases are often aggressive and require swift
evaluation for HCT while concurrently attempting to establish disease control through
the administration of standard therapies. If ongoing therapy for the underlying
disease outside of the NIH is not in the best interest of the subject according to the
clinical judgment of the PI, then the subject may receive standard treatment for
his/her underlying TCP/D disorder as a bridge to HCT on this protocol, prior to
starting the research phase of the study. If it becomes apparent that the subject will
not be able to proceed to HCT, then he/she must come off study. Subjects 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:

- Subjects 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 HCT.

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

- Active psychiatric disorder which is deemed by the PI to have significant risk of
compromising compliance with the transplant protocol or which does not allow for
appropriate informed consent

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

- MagT1 mutation and active need to take anti-platelet agents and/or therapeutic anti-
coagulation that cannot be interrupted during aplasia

INCLUSION CRITERIA - RELATED 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, and DR loci that is shared
with the recipient by high resolution typing, excluding an identical twin, or
unrelated donors matched 7-8/8 at HLA-A, B, C, and DR 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: No history of opportunistic infections, autoimmunity,
hemoglobinopathy, red cell enzymopathy, or malignancy, apart from non- melanomatous
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 for recipients who have germline monogenetic mutations as the cause of
their TCP/D disorder 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 should be
performed by a CLIA-certified lab, if such testing is available. For donors who carry
one wild type allele and one mutated allele of the disorder of TCP/D 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 may need to be verified through disease-appropriate
quantitative and functional assays to assess the function of the potential donor s
immune system.

Furthermore, the X-chromosome inactivation pattern may need to be assessed for female
carriers of X-linked diseases if the disease is not one where complete favorable
lyonization is not universal and if they are considered as potential donors, to confirm
favorable and complete lyonization of hematopoietic cells. For disorders of TCP/D 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 mutation testing is not
available or the mutation underlying the disorder of TCP/D is not identified.

-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 - RELATED 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-HCT.

- Donor to which the recipient has donor-specific anti-HLA antibodies and reduction of
recipient anti-HLA alloantibodies cannot be attempted or, if attempted, successfully
achieved.

- 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 for clinical purposes of donor selection. 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. Unrelated donors only enroll if
they contribute research specimens, which is optional.

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/. Exceptions to donor
eligibility (e.g. foreign travel, tattoos) do not automatically exclude the donor and will
be reviewed by the PI.