Skip to main content

Allogeneic Hematopoietic Stem Cell Transplant for People With Primary Immunodeficiency Diseases

Trial Status: Active

Background: During a transplant, blood stem cells from one person are given to someone else. The cells grow into the different cells that make up the immune system. This can cure people with certain immunodeficiencies. But transplant has many risks and complications. Objective: To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them. Eligibility: People ages 4-69 for whom a primary immunodeficiency (PID) or Primary Immune Regulatory Disorder (PIRD), has caused significant health problems and either standard management has not worked or there are no standard management options, along with their donors Design: Donors will be screened under protocol 01-C-0129. They will donate blood or bone marrow. Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests CT or PET scans Before transplant, participants will have dental and eye exams. They will have a bone marrow biopsy. For this, a needle will be inserted through the skin into the pelvis to remove marrow. Participants will be hospitalized before their transplant. They will have a central catheter put into a vein in their chest or neck. They will get medications through the catheter to prevent complications. Participants will get stem cells through the catheter. They will stay in the hospital for at least 4 weeks. They will give blood, urine, bone marrow, and stool samples. They may need blood transfusions. They may need more scans. They will take more medications. Participants will have visits on days 30, 60, 100, 180, and 360, and 24 months after the transplant. Then they will have visits once a year for about 5 years

Inclusion Criteria

  • - INCLUSION CRITERIA: - Age >= 4 years and <= 69 yo with Weight >=12 kilograms - Mutation in a known monogenic Primary Immunodeficiency Disease (PID) gene or Primary Immune Regulatory Disorder (PIRD) performed by a CLIA certified laboratory, who have failed standard medical management, or when no standard medical management is available. OR - Patients without a known PID or PIRD mutation may be eligible if they have a clinical history that is characteristic of an individual with an immune defect including a history of infections requiring prolonged courses of therapy or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute basis for inclusion. - Availability of a 10/10 or 9/10 or 8/10 HLA-matched related or unrelated donor (if the mismatch is at DQ this will be considered an 8/8 matched donor), or a haploidentical related donor. - Karnofsky or Lansky performance status of >= 40% - Adequate end-organ function, as measured by: - Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to enrollment. - Creatinine: Adult patients: <= 2.0 mg/dl and creatinine clearance >=30 ml/min; Pediatric patients (<18 years old): creatinine < 1.5 mg/dL and a creatinine clearance, using the Schwartz Formula > 30 mL/min/1.73m^2. - Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST 5 times upper limit of normal. - Pulmonary function tests: FEV1 > 30% and DLCO >30%. Children who are unable to have DLCO assessed due to age, are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen. - Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document. For subjects <18 years old, their legal guardian must give informed consent. Pediatric patients will provide assent. - 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. - Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH, for a minimum of 100 days after transplant or longer, if there are complications. If outpatient in the first 100 days after transplant, patient must commit to having an adult caregiver with them at all times. EXCLUSION CRITERIA: - 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 HCT. - Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. - HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. - History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (steroids, cyclophosphamide, busulfan, sirolimus, 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 - Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued if the mother is treated with the study agents. - Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Maryland

Bethesda
National Institutes of Health Clinical Center
Status: ACTIVE
Contact: National Cancer Institute Referral Office
Phone: 888-624-1937

Background:

- With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS)

for patients with suspected primary immune deficiency or Primary Immune Regulatory

Disorder (PIRD), the number of recognized PID s and PIRD s has increased in recent years

to over 400 distinct immune defects.

- Allogeneic hematopoietic stem cell transplantation represents a potentially curative

therapy for many hematologic diseases.

- Hematopoietic stem cell transplant is now an accepted standard or an appropriate

experimental approach for treatment of an increasing number of PID

- The use of conditioning regimens containing high doses of alkylating agents, often in

combination with total body irradiation, are considered myeloablative and are essential

and for suppression of the host-versus-graft response to the donor stem cells (i.e.

rejection)

- We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell

transplantation (HSCT) using selected conditioning regimens and selected donor sources

in reconstituting normal hematopoiesis and immune function and reversing the disease

phenotype in patients with primary immunodeficiency diseases.

Objectives:

-To determine whether allogeneic HSCT results in sustained donor engraftment defined as

neutrophil recovery with ANC greater than or equalto 500/mm(3) for 3 consecutive days

associated with > 50% donor T-cell and myeloid cell donor chimerism before day 100 for

diseases characterized by loss of function and >75% donor T-cell and myeloid cell chimerism

for diseases characterized by gain-of-function mutations.

Eligibility:

- Participants ages 4-69 years old with a known PID or PIRD, or with clinical evidence of

a PID or PIRD with a history of recurrent infections requiring prolonged courses of

therapy, or evidence of immune dysregulation manifested by autoimmune/autoinflammatory

disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired

response to vaccination. A virally-driven malignancy alone will also constitute a basis

for inclusion.

- Have a 10/10 or a 9/10 or 8/10 HLA-matched related or unrelated donor (HLA -A, -B, -C,

DRB1, DQB1 by high resolution typing) or a haploidentical related donor; unrelated

donors are identified through the National Marrow Donor Program.

Design:

For Recipients with Matched Donors

- Patients with PID receiving a high intensity transplant conditioning regimen will

receive a regimen consisting of fludarabine 40 mg/m(2) IV once daily for 4 days on days

-6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, -3 (busulfan

dose will be based on pharmacokinetic levels from the test dose and will be targeted to

an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the

default dose), and HSCT on day 0.

- Patients with PID receiving an intermediate intensity transplant conditioning regimen

will receive a regimen consisting of of fludarabine 40 mg/m(2) IV once daily for 4 days

on days -6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, -and -4

(busulfan dose will be based on pharmacokinetic levels from the test dose and will be

targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day

will be the default dose), and HSCT on day 0.

- Patients with PID receiving a low intensity transplant conditioning regimen will receive

a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5,

-4, and -3, busulfan IV once daily for 2 days on days -6, and -5 (busulfan dose will be

based on pharmacokinetic levels from the test dose and will be targeted to an AUC of

3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default

dose), and HSCT on day 0.

In all cohorts, patients with clinical evidence of immune dysregulation, alemtuzumab will be

given at the dose of 0.03 mg on day -11, 0.1 mg/kg on day -10, and 0.2 mg/kg on days -9 and

-8.

For Recipients with 9/10 or 8/10 Matched Donors and Haploidentical Related Donors

- Patients with PID receiving a high intensity transplant conditioning regimen will

receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days

-6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, and -4 (busulfan

dose will be based on pharmacokinetic levels from the test dose and will be targeted to

an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the

default dose), 200 cGy TBI on day -1, and HSCT on day 0.

- Patients with PID receiving an intermediate intensity transplant conditioning regimen

will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on

days -6, -5, -4, -and 3, busulfan IV once daily for 2 days on days -6, -and -5 (busulfan

dose will be based on pharmacokinetic levels from the test dose and will be targeted to

an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the

default dose), 200 cGy TBI on day -1, and HSCT on day 0.

- Patients with PID receiving a low intensity transplant conditioning regimen will receive

a regimen consisting of fludarabine 40 mg/m(2) IV once daily for 4 days on days -6, -5,

-4, and -3, busulfan IV once daily for 1 day on day -6 (busulfan dose will be based on

pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400

microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), 200

cGy TBI on day -1, and HSCT on day 0.

In all cohorts, patients with clinical evidence of immune dysregulation, alemtuzumab will be

given at the dose of 0.03 mg/kg on day -11, 0.1 mg/kg on day -10, and 0.2 mg/kg on days -9

and -8.

For Post-Transplant GVHD Prophylaxis

-Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV

once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to

approximately day +35 and tacrolimus from day +5 to approximately day +180. If there is no

evidence of GVHD, tacrolimus will be stopped or tapered at approximately day +180.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
National Cancer Institute

Principal Investigator
Dennis D. Hickstein

  • Primary ID 200070
  • Secondary IDs NCI-2020-02613, 20-C-0070
  • Clinicaltrials.gov ID NCT04339777