Outcomes in hematopoetic cell transplantation in the setting of mold infections in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a disorder of immunity characterized by phagocyte dysfunction. Mold infections in patients with CGD are often severe and disseminated. We present patient characteristics, microbiological data, and outcomes for 26 patients with CGD who received hematopoietic cell transplantation (HCT) or gene therapy-modified cells (GT) between 2008 and 2019, with proven fungal infection either before or during their transplant.

Outcomes of Related and Unrelated Donor Searches Among Patients with Primary Immunodeficiency Diseases Referred for Allogeneic Hematopoietic Cell Transplantation.

Patients with primary immunodeficiencies (PIDs) are potentially cured by allogeneic hematopoietic cell transplantation (HCT). The spectrum of PIDs has expanded greatly beyond those that present in infancy or are diagnosed on newborn screening and require urgent, preemptive HCT. Many PID diagnoses are now made later in life, and the role of HCT is only considered for severe disease manifestations; in these cases, the kinetics and goals of a donor search may be different than for severe combined immunodeficiency.

Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial.

Purpose: The purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center.

Methods: Forty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs.

Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in a Patient with Chronic Granulomatous Disease and Active Infection: A First Report.

Purpose: We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-transplant cyclophosphamide (PTCy) in a boy with x-linked chronic granulomatous disease (CGD).

Methods: A persistent and life-threatening fungal infection was the indication for HSCT. Non-myeloablative conditioning with PTCy (50 mg/kg days 3 and 4) was used in the absence of fully matched donors.

Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings.

Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations.

Common severe infections in chronic granulomatous disease.

Background: Chronic granulomatous disease (CGD) is due to defective nicotinamide adenine dinucleotide phosphate oxidase activity and characterized by recurrent infections with a limited spectrum of bacteria and fungi as well as inflammatory complications. To understand the impact of common severe infections in CGD, we examined the records of 268 patients followed at a single center over 4 decades.

Methods: All patients had confirmed diagnoses of CGD, and genotype was determined where possible.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A).

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.

WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4(R334X), in a phase 1 dose-escalation study.

AMD3100 is a potent antagonist at CXCR4(R334X) , a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome.

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild-type CXCR4 (CXCR4(WT)) and the most common WHIM variant of CXCR4 (CXCR4(R334X)), as well as leucocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls.