Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning With h-ATG, Radiation, and Sirolimus

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Brief Title

Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning With h-ATG, Radiation, and Sirolimus

Official Title

Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning With h-ATG, Radiation, and Sirolimus

Brief Summary


      Severe combined immune deficiency (SCID) is a group of conditions where the immune system
      does not work properly. The only cure for most SCIDs is a stem cell transplant (getting cells
      from a donor). These transplants can have serious complications. Before the transplant,
      people often get high doses of drugs and radiation to prepare the body to accept the cells
      from the donor. Researchers want to see if low doses of drugs alone without radiation work
      just as well as low doses of drugs with radiation for SCID patients getting stem cell


      To test a set of drugs with or without radiation given before a stem cell transplant.


      People ages 3-40 who have SCID and who have a stem cell donor - either related or unrelated.


      Participants will be admitted to the hospital 10 days before transplant. They will undergo:

      medical history

      medication review

      physical exam

      blood and urine tests (may include a 24-hour urine collection)

      heart, lung, and breathing tests

      imaging scans

      bone marrow sample

      nutrition assessment

      dental exam

      eye exam

      meeting with a social worker.

      Participants will get a plastic port called a central line. It is a hollow tube that is
      placed in the upper chest. It will be used to give medicines and take blood.

      All participants will take chemotherapy drugs. Some will get radiation.

      Participants will have a stem cell transplant. They will get the cells as an infusion through
      their central line. They will stay in the hospital for 30 days after transplant.

      Participants must stay within 1 hour of NIH for 3 months after transplant. During this time,
      they will have follow-up visits at NIH at least once a week. Then they will have follow-up
      visits once or twice a year for 5-6 years.

Detailed Description

      This is an open-label pilot study of human leukocyte antigen (HLA)-matched related and
      unrelated donor hematopoietic stem cell (HSC) transplant (also referred to as peripheral
      blood stem cell [PBSC] transplant or bone marrow transplant [BMT]) for up to 20 patients with
      severe combined immune deficiency (SCID). SCID is most commonly caused by mutations in the
      IL2RG gene encoding the interleukin (IL) receptor signaling gamma chain (gamma c); however,
      patients with JAK-3 mutations have the same phenotypes and are similarly affected. The study
      population is older children (greater than or equal to 3 years of age) and adults (less than
      or equal to 40 years of age) who are experiencing deteriorating and/or dysfunctional immunity
      and/or any of a constellation of severe or chronic medical problems warranting
      transplantation. The study is designed to evaluate whether the use of uniquely designed
      transplant conditioning either containing total body irradiation (TBI) or not, along with a
      graft-versus-host disease (GvHD) prevention regimen achieves sufficient engraftment of donor
      HSCs to facilitate robust restoration of cellular immunity (T cell/natural killer [NK] cell
      number and function) including thymic function, and humoral immunity (B cell number and
      function), while at the same time enhancing tolerance of the donor graft in a fashion that
      reduces the occurrence of GvHD but not significantly enhancing the risk of post-transplant
      viral infection. One target population is SCID patients who received matched sibling or
      haploidentical lymphocyte-depleted transplants as infants with little or no myeloid
      conditioning, resulting in variable restoration of T cell immunity, but little or no
      restoration of NK or B cell immunity. Another target population is SCID patients with partial
      production or function of gamma c or JAK3 or SCID patients with clonal somatic reversion of
      the mutation in the IL2RG or JAK-3 gene, who have less severe immune deficiency in childhood.
      A subset of patients from all of these target SCID populations may experience progressive
      deterioration of immune function leading to acute and chronic medical problems that warrant
      consideration of allogeneic transplant to restore immunity.

      The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed
      to use mobilized PBSCs or bone marrow (if mobilization is not possible) from either an
      HLA-matched related donor (MRD) as first choice or from an HLA-matched unrelated donor (MUD)
      for those without an appropriate HLA-MRD. If there is no appropriate MRD nor MUD adult donor
      available, then an appropriate cord blood from the cord blood registries may be used for
      small children SCID recipients. We propose using a busulfan-based, nonmyeloablative
      conditioning regimen plus or minus TBI combined with horse anti-thymocyte globulin (h-ATG)
      immune suppression conditioning plus post-transplant sirolimus as a tolerance-inducing
      immunosuppressant to prevent GvHD.

Study Phase

Phase 1/Phase 2

Study Type


Primary Outcome

Engraftment rate of > 80%

Secondary Outcome

 Donor B cell engraftment


Severe Combined Immunodeficiency (SCID)



Study Arms / Comparison Groups

 Group 1
Description:  Patients will be treated with Total Body Irradiation (TBI)


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

May 12, 2021

Completion Date

September 9, 2026

Primary Completion Date

September 9, 2026

Eligibility Criteria


          -  Must have confirmed genetic diagnosis of SCID (gamma c or JAK3 deficiency) by
             identification of a mutation in the responsible genes or by demonstrating failure to
             detect gamma c or JAK3 in immune blood cells (as in the case of patients who have been
             treated but now have waning immunity).

          -  Must have either evidence of waning immunity by T cell analysis, and/or sufficient
             complications from underlying disease to warrant undergoing transplantation as defined
             as meeting greater than or equal to1 of the following clinical criteria:

             i- Infections (not including molluscum, warts, or mucocutaneous candidiasis; see vii
             and viii below): 3 significant new or chronic active infections during the 2 years
             preceding evaluation for enrollment, with each infection accounting for one criterion.

        Infections are defined as an objective sign of infection (fever >38.3 (Infinite)C [101
        degrees F] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging
        evidence or typical lesion or histology or new severe diarrhea or cough with sputum
        production). In addition to one or more of these signs/symptoms of possible infection,
        there also must be at least 1 of the following criteria as evidence of the attending
        physician s intent to treat a significant infection (a and b) or objective evidence for a
        specific pathogen causing the infection (c):

          1. Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral
             antibiotics for greater than or equal to 14 days; OR

          2. Hospitalization of any duration for infection; OR

          3. Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal
             washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of

        ii. Chronic pulmonary disease as defined by:

          1. Bronchiectasis by x-ray computerized tomography; OR

          2. Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is
             less than or equal to 60% of predicted for age; OR

          3. Pulse oximetry less than or equal to 94% in room air (if patient is too young to
             comply with performance of PFTs).

        iii. Gastrointestinal enteropathy:

          1. Diarrhea-watery stools greater than or equal to 3 times per day (of at least 3 months
             duration that is not a result of infection as defined in criterion # i. above); OR

          2. Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be
             performed if medically indicated); OR

          3. Other evidence of enteropathy or bacterial overgrowth syndrome, including at least one
             of the following: malabsorption of fat soluble vitamin(s), abnormal D-xylose
             absorption, abnormal hydrogen breath test, or evidence of protein-losing enteropathy
             (for example, increasingly high or frequent dosing of IV gamma globulin supplement
             required to maintain blood IgG level).

        iv. Poor nutrition: Requires G-tube or IV feeding supplement to maintain weight or

        v. Auto- or allo-immunity: Objective physical findings including but are not limited to at
        least one of the following: alopecia, severe rashes, uveitis, joint pain with redness or
        swelling or limitation of movement that is not a result of infection, lupus-like lesions,
        and granulomas (not including auto- or alloimmune enteropathy, which is criterion iii).
        Where possible and appropriate, diagnosis will be supported by histopathology or another
        diagnostic modality.

        vi. Failure to grow in height: less than or equal to 3rd percentile for age.

        vii. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists
        of greater than or equal to 10 lesions or there are greater than or equal to 2 lesions at
        each of two or more widely separated anatomic sites; or there are greater than or equal to
        3 warts at different anatomic sites at the same time; or the patient has both molluscum and

        viii. Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida
        intertriginous infection or candida nail infection; must be culture positive to satisfy
        this criterion).

        ix. Hypogammaglobulinemia: Requires regular IgG supplementation.

          -  Aged 3-40 years, inclusive.

          -  Must have a 6/6 HLA-MRD graft available, or an HLA-matched unrelated PBSC graft (10/10
             or 9/10 mismatch) available, or a minimum of 4/6 HLA-matched cord blood product
             available (if the cord blood graft is less than 5.0x10(7) cells, a second appropriate
             4/6 or greater match cord blood product must be available).

          -  Mismatched MUD and Cord Blood transplants need to have Class I and II HLA antibody
             screen, DSA should be avoided.

          -  Must be HIV negative.

          -  Must be able to stay within 1 hour s travel of the NIH for the first 3 months after
             transplantation and have a family member or other designated companion to stay with
             during the post-transplant period.

          -  Must provide a durable power of attorney (DPA) for health care decisions to an
             appropriate adult relative or guardian in accordance to NIH-200 NIH Advance Directive
             for Health Care and Medical Research Participation .

          -  For participants of reproductive potential, must agree to consistently use highly
             effective contraception throughout study participation and for at least 3 months after
             the study.

        Acceptable forms of contraception are:

        a. For females:

        i. Condoms, male or female, with or without a spermicide;

        ii. Diaphragm or cervical cap with spermicide;

        iii. Intrauterine device;

        iv. Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA-approved
        contraceptive method;

        v. Male has previously undergone a vasectomy.

        b. For males: Condoms or other contraception with partner.


          1. Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 or
             more (see ECOG performance status guidelines, available at https://ecog-acrin.


          2. Left ventricular ejection fraction <40%.

          3. Transaminases >5x upper limit of normal based on the patient s clinical situation and
             at the discretion of the investigator.

          4. Liver alkaline phosphatase >10x upper limit of normal based on the patient s clinical
             situation and at the discretion of the investigator.

          5. Psychiatric disorder or mental deficiency severe enough as to make compliance with the
             BMT treatment unlikely, and/or making informed consent impossible.

          6. Major anticipated illness or organ failure incompatible with survival from alloPBSC,
             MUD, or unrelated cord blood transplant.

          7. Uncontrolled seizure disorder.

          8. Any condition that, in the opinion of the investigator, contraindicates participation
             in this study.

          9. Pregnant or lactating females.


        Children: Children 3 years of age and older may enroll on this study because the condition
        under study affects children and the study holds the prospect for direct benefit.

        Pregnant and Lactating Women: Pregnant women are excluded from this study due to risks
        associated with the study intervention and the effects of the combination of conditioning
        medications (h-ATG, busulfan) and total body irradiation on the developing human fetus,
        including potential teratogenic or abortifacient effects.

        If a study participant or partner of a male subject becomes pregnant or suspects she is
        pregnant, the participant should notify the study staff immediately. A female participant
        who becomes pregnant will be withdrawn from the study as outlined below. If a female
        participant or a partner of a male participant becomes pregnant, the participant will have
        contact follow-up with the study team to document the outcome of the pregnancy.

        Because there is an unknown but potential risk for AEs in nursing infants secondary to the
        mother undergoing the study intervention, breastfeeding should be discontinued if the
        mother will undergo the study intervention.

        Decisionally Impaired Adults: Adults who are unable to consent are eligible for enrollment
        in this protocol because they still benefit clinically from the study. However, the
        participant must have a DPA that can give consent. Similarly, enrolled participants who
        lose the ability to provide ongoing consent during study participation may continue in the
        study. The risks and benefits of participation for adults unable to consent should be
        identical to those described for less vulnerable patients.




3 Years - 40 Years

Accepts Healthy Volunteers



Elizabeth M Kang, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Study Sponsor

Elizabeth M Kang, M.D., Principal Investigator, National Institute of Allergy and Infectious Diseases (NIAID)

Verification Date

December 16, 2020