INCLUSION CRITERIA - RECIPIENT:
a) Patient age of 18-60 years
b) MonoMAC
1) Onset of immunodeficiency disease beyond infancy
2) Clinical history of at least two episodes of life-threatening infection with opportunistic organisms
3) Flow cytometry profile on peripheral blood leukocytes with:
-Absolute monocyte count less than 200 K/micro l (normal 300-820K/micro l)
-NK+ cell count less than 50 K/micro l (normal 87-505/micro l)
-CD20+ cell count less than 25 (normal 49-424/ micro l)
-CD3+ cell count greater than 100 (normal 650-2108/micro l)
c) Available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or greater) matched umbilical cord blood (UCB) unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg.
d) Patient may have evidence of MDS with one or more peripheral blood cytopenias and greater than 5% but less than 10% blasts in the bone marrow in the absence of G-CSF. Patients previously treated for acute myelogenous leukemia are eligible if they have less than or equal to 5% blasts in the bone marrow in the absence of G-CSF.
e) Left ventricular ejection fraction greater than 50%, preferably by 2-D echo, or by MUGA obtained within 28 days of enrollment
f) Corrected DLCO diffusion capacity and FEV1 greater than 10% of expected value obtained within 28 days of enrollment
g) Creatinine less than or equal to 2.0 mg/dl and creatinine clearance greater than or equal to 30 ml/min
h) Serum total bilirubin less than 2.5 mg/dl; serum ALT and AST less than or equal to 5 times upper limit of normal
h) Adequate central venous access potential
i) Written informed consent/assent obtained from patient/parent
j) Life expectancy of at least 3 months but less than 24 months
EXCLUSION CRITERIA- RECIPIENT:
a) HIV infection
b) Chronic active hepatitis B. Patient may be hepatitis B core antibody positive. For patients with a concomitant positive hepatitis B surface antigen, patients will require a hepatology consultation. The risk-benefit profile of transplant and hepatitis B will be discussed with the patient, and eligibility determined by the PI and the protocol chairperson
c) History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent
d) Active infection that is not responding to antimicrobial therapy.
e) Active CNS involvement by malignancy (patients with known positive CSF cytology or parenchymal lesions visible by CT or MRI).
f) Pregnant or lactating
g) Sexually active individuals capable of becoming pregnant who are unable or unwilling to use effective form(s) of contraception during time enrolled on study and for 1 year post-transplant. Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner's vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence. The effects on breast-milk are also unknown and may be harmful to the infant; therefore, women should not breast feed during the interval from study entry to one year post-transplant. Males on the protocol must use an effective form of contraception at study entry, and for one year post-transplant. The effects of transplant, the radiation, and the medications used after transplant may be harmful to a fetus.
h) Presence of active malignancy in another organ system other than the hematopoietic
i) No available 10/10 HLA-matched related or 8/8 matched unrelated donor, or 4/6 (or greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 times 10(7) TNC/kg.
INCLUSION CRITERIA- MATCHED RELATED DONOR:
a) Related donor matched at HLA-A, B, C, DR, and DQ loci by high resolution typing (10/10 antigen/allele match) are acceptable donors.
b) Ability to give informed consent.
c) Age 18-60 years.
d) No history of life-threatening opportunistic infection
e) Normal flow cytometry profile on peripheral blood leukocytes is required with a normal absolute monocyte count, and normal numbers of NK cells, B-lymphocytes, and T-lymphocytes.
f) Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
g) Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody negative. This is to prevent the possible transmission of these infections to the recipient.
h) A donor who is lactating must be willing and able to interrupt breast-feeding or substitute formula feeding for her infant during the period of filgrastim administration and for two days following the final dose. Filgrastim may be secreted in human milk, although its bioavailability from this source is not known. Limited clinical data suggest that short-term administration of filgrastim or sargramostim to neonates is not associated with adverse outcomes.
INCLUSION CRITERIA- MATCHED UNRELATED DONOR:
a) Unrelated donor matched at HLA-A, B, C, and DR loci by high resolution typing (8/8 antigen/allele match) are acceptable donors.
b) The evaluation of donors shall be in accordance with existing NMDP Standard Policies and Procedures. General donor inclusion criteria specified in the NMDP Standards.
EXCLUSION CRITERIA- MATCHED RELATED DONOR:
a) HIV infection
b) Chronic active hepatitis B. Donor may be hepatitis core antibody positive.
c) History of psychiatric disorder which in the opinion of the PI may compromise compliance with transplant protocol, or which does not allow to be appropriately informed
d) History of hypertension that is not controlled by medication, stroke, or severe heart disease. Individuals with symptomatic angina will be considered to have severe heart disease and will not be eligible to be a donor.
e) Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident).
f) History of prior malignancy. However, cancer survivors who have undergone potentially curative therapy may be considered for stem cell donation on a case-by-case basis. The risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time of transplantation will be discussed with the patient.
g) Donors must not be pregnant. Pregnancy is an absolute contraindication under this protocol. The effects of cytokine administration on a fetus are unknown. Donors of childbearing potential must use an effective method of contraception. Effective forms of contraception include one or more of the following: intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy, partner's vasectomy, barrier methods, (condom, diaphragm, or cervical cap), or abstinence.
h) Thrombocytopenia (platelets less than 150,000 per micro l) at baseline evaluation.
i) Donors receiving experimental therapy or investigational agents.
j) Sensitivity to filgrastim or to E. coli-derived recombinant protein products.
k) History of autoimmune disorders, including rheumatic diseases and thyroid disorders.
l) History of documented deep vein thrombosis or pulmonary embolism.
EXCLUSION CRITERIA- MATCHED UNRELATED DONOR:
Failure to qualify as an NMDP donor
INCLUSION CRITERIA- UMBILICAL CORD BLOOD UNIT-HLA TYPING AND DOSE
a) At least an HLA UCB 4/6 match (Class I-A, B by low resolution, and Class II-DR by high resolution) to recipient.
b) For Single UCB SCT: the unit will have greater than or equal to 3.5 times 10(7) TNC/kg of recipient body weight. Recipient body weight will be determined as per standard guidelines.
c) For Double UCB SCT: (done only if no single UCB unit greater than or equal to 3.5 times 10(7) NC/kg of recipient body weight is available. The larger of the two units (UCB1) will have a minimum cell dose of 2.0 times 10(7) TNC/kg of recipient body weight. The smaller of the two units (UCB2) will have a minimum of 1.5 X 10(7) TNC/kg of recipient body weight. The total cell dose UCB1 + UCB2 will be greater than or equal to 3.5 times 10(7)
d) For double UCB SCT each unit should be at least a 4/6 match (Class I-A, B by low resolution, Class II-DR by high resolution) to recipient, and should be at least a 4/6 match (Class I-A, B by low resolution, Class II-DR by high resolution) to each other.
National Institutes of Health Clinical Center
Bethesda, Maryland 20892. Last update: 11/25/2009