A Study of Treatment of Inflammation Before Stem Cell Transplant in People With a Primary Immune Regulatory Disorder (PIRD) and/or an Autoinflammatory Condition

Defects in the immune cells can hinder the immune system's ability to fight infection. A stem cell transplant can replace non-working immune system cells with a donor's fully functioning immune cells, but if inflammation is present, the immune cells from the donor may not graft successfully. The proposed trial tests whether emapalumab or fludarabine and dexamethasone can help prepare the body to receive a stem cell transplant by reducing inflammation, so that the immune system will be able to produce fully functioning immune cells. Participants will receive emapalumab or a combination of fludarabine and dexamethasone over the course of four days in the hospital prior to a planned transplant procedure.

This study has two study groups:

• Participants in Group A have a high CXCL9, a specific cytokine, level and will receive emapalumab on Days -22, -15, -8, and -1.
• Participants in Group B have a generalized inflammation and will receive fludarabine and dexamethasone from Days -22 to -18 (5 days).

All study participants are eligible to receive one additional emapalumab 3mg/kg in the first 30 days post-transplant if they begin to have CXCL9 levels that are trending up. Participants will receive personalized rATG dosing. Participants will remain in the hospital according to the usual standard of care guidelines for stem cell transplant. Subject status and follow-up examination/data collection will occur on days 0, 7, 14, 21,30, 45, 60, 7, 100, 180, 270, and 365, then quarterly until 3 years post-transplant.

Inclusion criteria

• Patients receiving first allo-HCT for the following immunologic conditions:

• Primary Immune Regulatory Disorder with or without a genetic lesion as defined by the Primary Immune Deficiency Treatment Consortium (PIDTC)12 - Patients with autoinflammatory disorders evidenced by cytokine or inflammation assays with at least 1.5x ULN of measured cytokines (defined in section 4) and/or an elevated ferritin or ESR > 2 ULN
• For inclusion on the emapalumab group, the lesion must be related to the IFNγ pathway (or mediators thereof) with an elevated CXCL9 >1.5 ULN OR sIL2R >1.5 ULN (or already controlled on immune modulation, provided that CXCL9 or sIL2R levels were elevated prior to initiation of immune modulation).
• Inclusion on the Fludarabine/dexamethasone group requires inflammation (as defined above) other than an IFNy pathway defect
• Able to tolerate cytoreduction (based on adequate organ function as described below)
• Patients of any age can enroll so long as they meet all other eligibility criteria
• Adequate organ function is required, defined as follows:

• Hepatic: Serum bilirubin ≤ 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders related to their PIRD diagnosis are eligible.
• Hepatic: AST, ALT, and alkaline phosphatase < 2.5 times the upper limit of normal unless thought to be disease-related. Investigator will need to perform clinically indicated evaluations to assess if disease related or intrinsic liver disease. Additional testing may be done if clinically indicated, after the pre-transplant immune prophase and prior to start of conditioning as this will provide additional data to confirm disease related versus intrinsic liver dysfunction.
• Renal: serum creatinine <1.5x normal for age. If serum creatinine is outside the normal range, then CrCl > 50 mL/min/1.73m^2 (calculated or estimated) or GFR (mL/min/1.72m^2) >30% of predicted normal for age.
• Cardiac: LVEF ≥ 50% by MUGA or resting echocardiogram.
• Pulmonary: Pulmonary function testing (FEV1 and corrected DLCO) ≥ 50% predicted (pediatric patients unable to complete PFTs will need oxygen saturation as recorded by pulse oximetry of ≥92% on room air).
• Adequate performance status:

• Age ≥ 16 years: ECOG ≤ 1 or Karnofsky ≥ 70%
• Age < 16 years: Lansky 70%
• Each patient must be willing to participate as a research subject and must sign an informed consent form or legal guardian with assent as appropriate.

Donor Inclusion Criteria:

• Related Donors:

• 8/8 or 7/8 HLA matched at A, B, C, and DRB1 loci, as tested by DNA analysis.
• Haploidentical donors at A, B, C and DRB1 loci, as tested by DNA analysis
• Unrelated Donors:

• 8/8 or 7/8 matched at A, B, C, and DRB1 loci, as tested by DNA analysis.
• Able to provide informed consent for the donation process per institutional standards.
• Meet standard criteria for donor collection (e.g. National Marrow Donor Program Guidelines or collecting center guidelines as approved by treating physician).

Exclusion criteria

• Uncontrolled infection at the time of enrollment.
• Patients who have undergone previous allo-HCT.
• Patient seropositivity for HIV I/II and/or HTLV I/II.
• Females who are pregnant or breastfeeding.
• Patients unwilling to use contraception during the study period.
• Patient or parent or guardian unable to give informed consent or unable to comply with the treatment protocol including research tests.