Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity

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.

• INCLUSION CRITERIAl:
• 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:

--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 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.