Table 1.
Patient demographics and transplant characteristics
| Pt | Diagnosis | Genetic mutation | Age at diagnosis, y | Age at HSCT/ sex | Medical complications prior to transplant | HCT-CI score* | Donor (HLA mismatch) | Stem cell source | CD34 dose, ×106/kg | CMV status (R/D) | Conditioning regimen | In vivo T-cell depletion (dose) | GVHD prophylaxis |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | CVID | Not done. | 20 | 31/F | Red cell aplasia. | 2 | MRD | PBSC | 10.8 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 2 | Granulomatous CVID | No mutation in TNFSF5. (Normal T-cell numbers at presentation and no T-cell related infections). | 15 | 30/F | Inflammatory lung disease, sclerosing cholangitis, prior splenectomy, pulmonary fibrosis, pulmonary aspergilloma,* osteopenia. | ≥3 | MUD | PBSC | 15.3 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 3 | APDS2 | Splice donor mutation in PIK3R1 (predicting exon skipping). | 10 | 50/M | Severe lymphatic pancolitis, previous mycoplasma arthritis, bronchiectasis, previous peripheral CD8+ T-cell NHL, pulmonary hypertension. | ≥3 | MUD | PBSC | 5.1 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 4 | Autoimmune LPD | Heterozygous TNFRSF 6 gene encoding Fas (c.785T>C (I232T). | 3 | 32/M | Refractory thrombocytopenia, previous splenectomy, hypertension. | 2 | MRD | PBSC | 3.7 | +/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 5 | Autoimmune LPD | No mutation identified, including in Fas, SH2D1A. Functional apoptosis defect. | 32 | 34/M | Indolent lymphoma (NHL), autoimmune neutropenia, MGUS with IgG paraprotein, previous splenectomy, factor XI deficiency. | 1 | MUD | PBSC | 6.7 | −/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 6 | Cγ-chain SCID | Confirmed by sequencing. | 1 | 26/M | Failed haploidentical allo and gene therapy. Sclerosing cholangitis. Recurrent infections. Bronchiectasis and pneumocele. Brachiocephalic thrombus. Hepatomegaly with chronic cholangiopathy. Refractory facial planar warts. Depression. | ≥3 | MUD | PBSC | 12.6 | +/+ | Flu Mel | Alemuzumab (100 mg) | CSA |
| 7 | Absolute NK deficiency, hypogammaglobulinemia | No mutation identified. Whole-genome sequencing pending. | 14 | 27/M | Refractory planar warts (HPV2),† recurrent infections, bronchiectasis, sarcoid arthropathy, IgG 1 and 2 subclass deficiency. | ≥3 | MRD | PBSC | 7.8 | +/+ | Flu Mel | Alemtuzumab (30 mg) | CSA |
| 8 | DCML deficiency | Gata2 wild type; whole-exome sequencing. Pending. | 24 | 27/F | Trilineage MDS, bronchiectasis, Crohn colitis, recurrent viral warts, Mycobacterium avium complex, AIN and vulval intraepithelial neoplasia (HPV)†. | ≥3 | MMUD (C Ag) | PBSC | 6.3 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 9 | AR IL12Recβ deficiency | Confirmed by sequencing. | 19 | 29/M | Recurrent Salmonella sepsis, Salmonella pericarditis with cardiac tamponade, mild asthma, recurrent otitis externa. | ≥3 | MMUD (A Ag) | PBSC | 7.0 | −/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 10 | Rag2/red cell aplasia | RAG2 (c.104G>T (Gly35Val)/het and c.814G>A (Val72Ile)/het andc.965T>C(Met 322Thr)Het. | 16 | 20/M | Red cell aplasia, granulomatous skin lesions, high transfusion requirement and iron overload, chronic clonal NK-cell proliferation, EBV viremia. | ≥3 | MUD | PBSC | 5.4 | −/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 11 | X-linked LPD | Confirmed by sequencing. | 3 | 18/M | B-cell NHL, hypogammaglobulinemia. | 1 | MRD | PBSC | 11.0 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 12 | Undefined CID | c.205del heterozygote in CD27 gene. Heterozygous mutations in CD27, LRBA, LYST, and PRKDC. | 11 | 22/M | EBV viremia, atypical stage 4B T-cell rich B-cell NHL, LP HL (R-CHOP ×6, high dose MTX). | 2 | MUD | PBSC | 4.0 | +/+ | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 13 | CD27 deficiency | CD27 (c.251_252insT [C71Lfs*4] and SNP in exon 3 371761387). | 13 | 18/M | Nodular sclerosing HL, EBV+ stage IV diffuse large B-cell lymphoma. | 1 | MMUD (A Ag) | PBSC | 6.4 | −/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 14 | Gata2 deficiency | 735-736insC amino acid Subs P245fs. | 20 | 22/F | MDS, persistent viral warts, mild IgG hypogammaglobulinemia, CD19, CD56 lymphopenia, HPV VIN3†. | 1 | MUD | PBSC | 6.3 | +/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 15 | XIAP deficiency | XIAP: absent by FACs (2 centers); no mutation identified. | 19 | 21/M | HLH, Crohn (requiring pancolectomy as a child). | ≥3 | MRD | PBSC | 4.7 | −/+ | Flu Mel | Alemtuzumab (30 mg) | CSA |
| 16 | Autoimmune LPD | I246T Fas mutation. | 2 | 21/F | Relapsed Hodgkin lymphoma, autoimmune hemolysis, genital HSV, previous splenectomy, juvenile inflammatory arthropathy, patchy colonic lymphocytic infiltration. | 2 | MRD | PBSC | 2.1 | +/+ | Flu Mel | Alemtuzumab (30 mg) | CSA |
| 17 | Gata 2 mutation | Frame duplication of 6 nucleotides not previously reported. | 19 | 22/F | MDS with profound monocytopenia, prolonged severe EBV infection with hepatitis and meningoencephalitis. | ≥3 | MRD | PBSC | 2.0 | −/− | Flu Mel | Alemtuzumab (30 mg) | CSA |
| 18 | XIAP deficiency | Sequence variant c.497G>A in exon 2 of the XIAP gene. Not previously reported. | 4 | 24/M | EBV lymphoproliferative disease ×2 episodes, hypogammaglobulinemia, splenomegaly, granulomatous lymphocytic inflammatory lung disease with bronchiectasis. | 2 | MRD | PBSC | 5.5 | +/− | Flu Mel | Alemtuzumab (30 mg) | CSA |
| 19 | AR-CGD | P47 deficiency identified on FACs analysis. | 12 | 18/M | Recurrent infections including staphylococcal abscesses. | 1 | Father 10/10 | BM | 3.7 | +/+ | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 20 | AR-CGD | p47 deficiency identified on FACs analysis. | 18 | 19/M | Recurrent infections, chronic relapsing multifocal osteomyelitis, mold pulmonary infection, dyslexia. | 2 | MUD | BM | 2.1 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 21 | AR-CGD | NCF-1 (P47 deficiency by FACs. Homozygous for c.579g>A (Trp193X). | 3 | 27/F | Recurrent infections including presumed nocardia meningitis. Severe inflammatory bowel disease necessitating subtotal colectomy and ileostomy formation. Colonized with resistant Pseudomonas. | ≥3 | MUD | BM | 6.3 | +/+ | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 22 | Variant CGD | NCF-1 (fusion of NCF-1 and pseudo NCF-1 with crossover between exon 4 and exon 16). | 24 | 28/F | Severe Crohn disease with perineal and perianal disease requiring colectomy and proctectomy with ileostomy. | 1 | MUD | PBSC | 14.5 | −/− | Flu Bu | rATG (7.5 mg/kg) | CSA |
| 23 | X-linked CGD | CYBB (c.G764A[Trp251*]). | 1 | 27/M | Recurrent infections, severe colitis. | 2 | MRD | PBSC | 5.0 | +/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 24 | X-linked CGD | p47 deficiency identified on FACs analysis. | 2 | 18/M | Pancolitis, previous hemicolectomy for stricture of ascending colon, recurrent infections, renal impairment. | ≥3 | MUD | BM | 4.2 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 25 | X-linked CGD | CYBB (TC342/343 > AT [His115Tyr]). | 4 | 19/M | Recurrent fungal chest infections, extensive granulomas, growth failure, previous gene therapy (August 2007) with transient engraftment. | ≥3 | MMUD (A Ag) | PBSC | 32.3 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 26 | X-linked CGD | GP91 intron6 gtg>atg. | 1 | 19/M | Recurrent infections including osteomyelitis and fungal chest infection (Aspergillus nidulans). | 1 | MMUD (A Ag) | BM | 0.3 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 27 | X-linked CGD | GP91phox 20-kb deletion leading to complete absence of CYBB and Kell genes (McLeod phenotype). | At birth | 17/M | Pancolitis, recurrent infections, McLeod phenotype. | 2 | MUD | BM | 1.4 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
| 28 | X-linked CGD | NCF1 (c.579G>A (TRP193*). | 16 | 23/M | Recurrent infections including staphylococcal skin abscesses, progressive granulomas. | 2 | MRD | PBSC | 4.1 | +/− | Flu Mel | Alemtuzumab (100 mg) | CSA |
| 29 | X-linked CGD | Gp91absent by FACs. | 2 mo | 17/M | Progressive colitis, multiple infective complications. | 2 | MUD | BM | 1.9 | −/− | Flu Bu | Alemtuzumab (0.6 mg/kg) | CSA |
Ag, antigen; AIN, anal intraepithelial neoplasia; APDS2, activated phosphatidylinositol 3-kinase δ syndrome type 2; AR, autosomal recessive; BM, bone marrow; Bu, busulfan; CGD, chronic granulomatous disease; CID, combined immunodeficiency; CSA, cyclosporin A; CVID, common variable immunodeficiency; DCML, dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency; F, female; FACs, fluorescence-activated cell sorting; Flu, fludarabine; HCT-CI, hematopoietic cell transplant–comorbidity index; HL, Hodgkin lymphoma; HLH, hemophagocytic lymphohistiocystosis; HPV, human papilloma virus; HSV, herpes simplex virus; IgG, immunoglobulin G; LP HL, lymphocyte predominant HL; LPD, lymphoproliferative disease; M, male; MDS, myelodysplastic syndrome; Mel, melphalan; MGUS, monoclonal gammopathy of undetermined significance; MMUD, mismatched unrelated donor; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; NHL, non-Hodgkin lymphoma; NK, natural killer cell; PBSC, peripheral blood stem cell; Pt, patient; rATG, rabbit antithymocyte globulin; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R/D, recipient/donor cytomegalovirus serostatus; SCID, severe combined immunodeficiency; SNP, single-nucleotide polymorphism; XIAP, X-linked inhibitor of apoptosis protein deficiency.
*
Active infection at transplant.
†
Unresolved viral warts at transplant.