Lymphoproliferative DisordersPhase 2NCT04339777
Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
A Phase 2 study testing Busulfan test dose, Fludarabine and Busulfan in people with Lymphoproliferative Disorders and Autoimmune Lymphoproliferative, run by National Cancer Institute (NCI) at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 4 to 69 years
- Conditions the study is for
- Lymphoproliferative Disorders, Autoimmune Lymphoproliferative, Immune System Diseases
- What is being tested?
- Busulfan test dose, Fludarabine and Busulfan
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 66 participants
- Where
- 1 siteUnited States
- Study dates
- 22 Sep 2020to 30 Nov 2032
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 to 69 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Age >= 4 years and <=69 yo with Weight >=12 kilograms
- Mutation in a known monogenic (IEI) gene 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 IEI 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 an 8/8, 7/8, or 6/8 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:
Show all 14Show fewer
- --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.
Who cannot join
- Patients who are receiving any other investigational agents (with the exception of virus-specific therapy e.g. 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, tacrolimus, sirolimus, MMF, G-CSF, alemtuzumab) 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office, 888-624-1937
About this study
Official title: A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
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.
Read more
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
Read the detailed description
Background:
- With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected inborn errors of immunity (IEI), the number of recognized IEI has increased in recent years to over 400 distinct immune defects.
- Allogeneic hematopoietic stem cell transplantation (HSCT) 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 IEI
- We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with IEI.
Objectives:
-To determine whether allogeneic HSCT in patients with IEI results in sustained donor engraftment defined as neutrophil recovery with ANC >= 500/mm^3 for 3 consecutive days associated with > 50% donor T-cell and myeloid cell donor chimerism by 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 IEI, or with clinical evidence of an IEI 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 an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program.
Design:
For Recipients with Fully Matched Donors
- Patients with IEI 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 or real time pharmacokinetics (PKs) and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
- Patients with IEI 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 3 days on days -6, -5, -and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
-Patients with IEI 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 2 days on days -6, and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m^2 subcutaneously divided over 3 days, on days -14, -13 and -12.
For Recipients with 7/8 or 6/8 Matched Related or Unrelated Donors and Haploidentical Related Donors
- Patients with IEI 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, and -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (52-72 mg 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 IEI 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 3 days on days -6, -5, and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (39-54 mg 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 IEI 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 day -6 and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (26-36 mg 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, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m2 subcutaneously divided over 3 days, on days -14, -13 and -12.
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.
- Conditions
- Lymphoproliferative Disorders, Autoimmune Lymphoproliferative, Immune System Diseases, Common Variable Immunodeficiency, Primary T-cell Immunodeficiency Disorders
- Being tested
- Busulfan test dose, Fludarabine, Busulfan, Alemtuzumab, Total body Irradiation
- Keywords
- Autoimmunity, Haploidentical, Opportunistic Infection, Immune Dysregulation, Congenital
- Medical subject headings
- Lymphoproliferative Disorders, Immune System Diseases, Common Variable Immunodeficiency, T cell immunodeficiency primary, Autoimmune Diseases, Opportunistic Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Busulfan test doseDrug
0.8 mg/kg IV infusion over 2 hours
FludarabineDrug
40 mg/m2 IV infusion over 30 min once daily for 4 days
BusulfanDrug
AUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3).
For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4).
For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6,
-5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5).
For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6).
AlemtuzumabDrug
Alemtuzumab will be given if there is evidence of immune dysregulation 10 mg/m2 SC divided over three days (-14, -13, and -12)
Total body IrradiationRadiation
200 cGy Transplant Day -1 (Only for 9/10 HLA Matched Related or Unrelated Donor Recipients )
Allogeneic HSCTProcedure or surgery
Stem cell transplant
Tacrolimus (Tacro)Drug
Tacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5
Mycophenolate mofetil (MMF)Drug
Mycophenolate mofetil 15 mg/kg IV over 2 hours three times a day starting on day +5 will continue until Approximately+35 (+/- two days)
Cyclophosphamide (Cytoxan)Drug
Cyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight
| Study group | Role | What they receive |
|---|---|---|
| Arm A | Active comparator | Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Receives: Drug: Busulfan test dose; Drug: Fludarabine; Drug: Busulfan; Drug: Alemtuzumab; Procedure: Allogeneic HSCT; Drug: Tacrolimus (Tacro); Drug: Mycophenolate mofetil (MMF); Drug: Cyclophosphamide (Cytoxan) |
| Arm B | Active comparator | Intermediate Intensity Conditioning with or without Alemtuzumab Receives: Drug: Busulfan test dose; Drug: Fludarabine; Drug: Busulfan; Drug: Alemtuzumab; Radiation: Total body Irradiation; Procedure: Allogeneic HSCT; Drug: Tacrolimus (Tacro); Drug: Mycophenolate mofetil (MMF); Drug: Cyclophosphamide (Cytoxan) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sustained donor engraftment
neutrophil recovery with ANC >/= 500/mm^3 for 3 consecutive days with >50% or >75% T-cell and myeloid donor chimerism
Measured: baseline to day +100
Secondary outcomes (8)
Reversal of the immunological abnormalities
Cumulative correction of disease-specific immunological abnormalities by 1-5 years post transplant
Measured: 1 through 5 years post transplant
Reversal of the clinical phenotype
Cumulative improvement of clinical phenotype consistent with the replacement of hematopoietic cells at 1 -5 years post transplant
Measured: 1 and 2 years post transplant
regimen-related mortality
Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant
Measured: +180 and 1 year post transplant
Overall survival
Time from transplant to death of any cause
Measured: 1 through 5 years post transplant
infection and viral reactivation
Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant
Measured: +180 and 1 year post transplant
Incidence of Chronic Graft-versus-host disease
Cumulative incidence of chronic graft versus host disease at 1 and 2 years post transplant
Measured: 1 and 2 years post transplant
Incidence of Acute Graft-versus-host disease
Cumulative incidence of acute graft versus host disease at day 100 post transplant
Measured: 100 days post transplant
Event free survival
Time from transplant to death of any cause, primary or secondary graft failure, or second transplant
Measured: 1 through 5 years post transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2020
- Study start22 Sep 2020
- Primary completion1 Oct 2028 (estimated)
- Study completion30 Nov 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Lymphoproliferative DisordersStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 66 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Sung-Yun Pai, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04339777
- Sponsor's protocol ID
- 200070
- Other IDs
- 20-C-0070
- Status last verified
- 15 Oct 2026
- First submitted
- 8 Apr 2020
- Last updated
- 19 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD recorded in the medical record will be shared with intramural investigators upon request.
Publications
Arnold DE, Kaviany S, Aluri J, Calvo KR, Mehta SS, Tobin JM, Schuettpelz LG, Saucier N, Schmitz EG, Murguia-Favela L, Wright NAM, De Ravin SS, Rao VK, Holland SM, Bleesing JJ, Loughran TP Jr, Feith DJ, Powell J, Ratan A, Warren JT, Pai SY, Bednarski JJ, Connelly JA, Cooper MA. Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function. Blood Adv. 2026 Mar 24;10(6):1967-1976. doi: 10.1182/bloodadvances.2025016338.
PubMed 41370196
Study at a glance
From the registry record, last updated by the sponsor on 19 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
- ClinicalTrials.gov ID
- NCT04339777
- Acronym / sponsor ID
- 200070
- Conditions
- Lymphoproliferative Disorders, Autoimmune Lymphoproliferative, Immune System Diseases, Common Variable Immunodeficiency, Primary T-cell Immunodeficiency Disorders
- Keywords
- Autoimmunity, Haploidentical, Opportunistic Infection, Immune Dysregulation, Congenital
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 66 participants (estimated)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 22 Sep 2020 (actual)
- Primary completion
- 1 Oct 2028 (estimated)
- Study completion
- 30 Nov 2032 (estimated)
- First posted
- 9 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
Background:
- With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected inborn errors of immunity (IEI), the number of recognized IEI has increased in recent years to over 400 distinct immune defects.
- Allogeneic hematopoietic stem cell transplantation (HSCT) 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 IEI
- We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with IEI.
Objectives:
-To determine whether allogeneic HSCT in patients with IEI results in sustained donor engraftment defined as neutrophil recovery with ANC >= 500/mm^3 for 3 consecutive days associated with > 50% donor T-cell and myeloid cell donor chimerism by 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 IEI, or with clinical evidence of an IEI 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 an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program.
Design:
For Recipients with Fully Matched Donors
- Patients with IEI 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 or real time pharmacokinetics (PKs) and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
- Patients with IEI 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 3 days on days -6, -5, -and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
-Patients with IEI 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 2 days on days -6, and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m^2 subcutaneously divided over 3 days, on days -14, -13 and -12.
For Recipients with 7/8 or 6/8 Matched Related or Unrelated Donors and Haploidentical Related Donors
- Patients with IEI 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, and -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (52-72 mg 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 IEI 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 3 days on days -6, -5, and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (39-54 mg 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 IEI 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 day -6 and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (26-36 mg 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, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m2 subcutaneously divided over 3 days, on days -14, -13 and -12.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A | Active comparator | Drug: Busulfan test dose, Drug: Fludarabine, Drug: Busulfan, Drug: Alemtuzumab, Procedure: Allogeneic HSCT, Drug: Tacrolimus (Tacro), Drug: Mycophenolate mofetil (MMF), Drug: Cyclophosphamide (Cytoxan)Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab |
| Arm B | Active comparator | Drug: Busulfan test dose, Drug: Fludarabine, Drug: Busulfan, Drug: Alemtuzumab, Radiation: Total body Irradiation, Procedure: Allogeneic HSCT, Drug: Tacrolimus (Tacro), Drug: Mycophenolate mofetil (MMF), Drug: Cyclophosphamide (Cytoxan)Intermediate Intensity Conditioning with or without Alemtuzumab |
Who may qualify
- Ages
- 4 to 69 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (14 listed)
- Age >= 4 years and <=69 yo with Weight >=12 kilograms
- Mutation in a known monogenic (IEI) gene 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 IEI 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 an 8/8, 7/8, or 6/8 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%
Key exclusion criteria (7 listed)
- Patients who are receiving any other investigational agents (with the exception of virus-specific therapy e.g. 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, tacrolimus, sirolimus, MMF, G-CSF, alemtuzumab) 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Busulfan test dose0.8 mg/kg IV infusion over 2 hours | Drug | Arm A, Arm B |
| Fludarabine40 mg/m2 IV infusion over 30 min once daily for 4 days | Drug | Arm A, Arm B |
| BusulfanAUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3). For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4). For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6, -5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5). For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6). | Drug | Arm A, Arm B |
| AlemtuzumabAlemtuzumab will be given if there is evidence of immune dysregulation 10 mg/m2 SC divided over three days (-14, -13, and -12) | Drug | Arm A, Arm B |
| Total body Irradiation200 cGy Transplant Day -1 (Only for 9/10 HLA Matched Related or Unrelated Donor Recipients ) | Radiation | Arm B |
| Allogeneic HSCTStem cell transplant | Procedure or surgery | Arm A, Arm B |
| Tacrolimus (Tacro)Tacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5 | Drug | Arm A, Arm B |
| Mycophenolate mofetil (MMF)Mycophenolate mofetil 15 mg/kg IV over 2 hours three times a day starting on day +5 will continue until Approximately+35 (+/- two days) | Drug | Arm A, Arm B |
| Cyclophosphamide (Cytoxan)Cyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight | Drug | Arm A, Arm B |
Primary outcome
Sustained donor engraftment
Time frame: baseline to day +100
neutrophil recovery with ANC >/= 500/mm^3 for 3 consecutive days with >50% or >75% T-cell and myeloid donor chimerism
8 secondary outcomes
Reversal of the immunological abnormalities
Time frame: 1 through 5 years post transplant
Reversal of the clinical phenotype
Time frame: 1 and 2 years post transplant
regimen-related mortality
Time frame: +180 and 1 year post transplant
Overall survival
Time frame: 1 through 5 years post transplant
infection and viral reactivation
Time frame: +180 and 1 year post transplant
Incidence of Chronic Graft-versus-host disease
Time frame: 1 and 2 years post transplant
Incidence of Acute Graft-versus-host disease
Time frame: 100 days post transplant
Event free survival
Time frame: 1 through 5 years post transplant
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Oct 2026.
- Derived from this study: PubMed 41370196Arnold DE, Kaviany S, Aluri J, Calvo KR, Mehta SS, Tobin JM, Schuettpelz LG, Saucier N, Schmitz EG, Murguia-Favela L, Wright NAM, De Ravin SS, Rao VK, Holland SM, Bleesing JJ, Loughran TP Jr, Feith DJ, Powell J, Ratan A, Warren JT, Pai SY, Bednarski JJ, Connelly JA, Cooper MA. Clinical characteristics, management, and hematopoietic cell transplantation of patients with TLR8 gain-of-function. Blood Adv. 2026 Mar 24;10(6):1967-1976. doi: 10.1182/bloodadvances.2025016338.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. All IPD recorded in the medical record will be shared with intramural investigators upon request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sung-Yun Pai, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Busulfan test dose, Fludarabine and Busulfan in people with Lymphoproliferative Disorders and Autoimmune Lymphoproliferative, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 19 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Shannon L Knight, R.N. ((240) 921-5872, shannon.knight@nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sustained donor engraftment (time frame: baseline to day +100). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04339777, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Oct 2026.