Key Points

  • Transplant survival for MHC class II deficiency has improved significantly in the modern era of HCT.

  • Long-term health outcomes after HCT for MHC class II expression deficiency are good.

Abstract

MHC class II deficiency is a rare, but life-threatening, primary combined immunodeficiency. Hematopoietic cell transplantation (HCT) remains the only curative treatment for this condition, but transplant survival in the previously published result was poor. We analyzed the outcome of 25 patients with MHC class II deficiency undergoing first HCT at Great North Children's Hospital between 1995 and 2018. Median age at diagnosis was 6.5 months (birth to 7.5 years). Median age at transplant was 21.4 months (0.1-7.8 years). Donors were matched family donors (MFDs; n = 6), unrelated donors (UDs; n = 12), and haploidentical donors (HIDs; n = 7). Peripheral blood stem cells were the stem cell source in 68% of patients. Conditioning was treosulfanbased in 84% of patients; 84% received alemtuzumab (n = 14) or anti-thymocyte globulin (n = 8) as serotherapy. With a 2.9-year median follow-up, OS improved from 33% (46-68%) for HCT before 2008 (n = 6) to 94% (66-99%) for HCT after 2008 (n = 19; P = .003). For HCT after 2008, OS according to donor was 100% for MFDs and UDs and 85% for HIDs (P = .40). None had grade III-IV acute or chronic graft-versus-host disease. Latest median donor myeloid and lymphocyte chimerism were 100% (range, 0-100) and 100% (range, 64-100), respectively. Latest CD4+ T-lymphocyte number was significantly lower in transplant survivors (n = 14) compared with posttransplant disease controls (P = .01). All survivors were off immunoglobulin replacement and had protective vaccine responses to tetanus and Haemophilus influenzae. None had any significant infection or autoimmunity. Changing transplant strategy in Great North Children's Hospital has significantly improved outcomes for MHC class II deficiency.

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Disclosures

Associate Editor Catherine M. Bollard served as an advisor or consultant for Cellectis, NovImmune SA, and Roche and owns stocks, stock options, or bonds from Cabaletta Bio, Mana Therapeutics, NexImmune Inc., and Torque Therapeutics. CME questions author Laurie Barclay, freelance writer and reviewer, Medscape, LLC and the authors declare no relevant financial relationships.

Learning objectives

Upon completion of this activity, participants will be able to:

  1. Describe transplant survival of children with major histocompatibility complex (MHC) class II deficiency transplanted at a single national center, according to a retrospective study

  2. Determine long-term disease outcomes of children with MHC class II deficiency transplanted at a single national center, according to a retrospective study

  3. Identify clinical implications of transplant survival and long-term disease outcomes of children with MHC class II deficiency transplanted at a single national center, according to a retrospective study

Release date: March 19, 2020; Expiration date: March 19, 2021

Introduction

Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive combined immunodeficiency.1  MHC class II genes are located on chromosome 6, and expression is largely restricted to activated T lymphocytes, thymic epithelial cells, and antigen-presenting cells (dendritic cells, macrophages, and B lymphocytes). In patients with MHC class II deficiency, the MHC locus itself is intact but transcriptionally silent because of loss-of-function mutations in 1 of 4 genes encoding the key regulatory factors: CIITA (class II transactivator), RFX5 (regulatory factor 5), RFXAP (RFX-associated protein), and RFXANK (RFX-associated ankyrin-containing protein). MHC class II molecules are pivotal for the adaptive immune system and guide the development and function of CD4+ T lymphocytes. The immunologic hallmark of the disease is the absence of constitutive and inducible expression of MHC class II molecules on all cell types, which leads to impaired antigen presentation by HLA-DR, HLA-DQ, and HLA-DP molecules on antigen-presenting cells.2  The lack of MHC class II expression on thymic epithelium leads to delayed and incomplete maturation of the CD4+ T-lymphocyte population. Overall, MHC class II deficiency leads to combined immunodeficiency with defective CD4+ T-lymphocyte maturation and activation and a lack of T-helper lymphocyte-dependent antibody production by B lymphocytes, resulting in significant susceptibility to severe infections.3 

Hematopoietic cell transplantation (HCT) is the only curative therapy for children with MHC class II deficiency. The natural history of nontransplanted patients is dismal, and the main cause of death is overwhelming viral infection.4  Very few children survive into adulthood.5  HCT for MHC class II deficiency is challenging because many children have significant comorbidities at the time of HCT, increasing their susceptibility to regimen-related toxicities, serious infections, graft rejection, and graft-versus-host disease (GvHD). Historically, the use of HCT has been limited because of the high risk of transplant-related morbidity and mortality. Reported transplant survival was poor compared with that seen in children with classical severe combined immunodeficiency (SCID), with a survival rate ≤ 50%.3,6-9  In light of the significant improvements in transplant care for children with primary immunodeficiency (PID) over time, the present retrospective study aimed to examine transplant survival and long-term disease outcomes of children with MHC class II deficiency transplanted at a single national center.

Methods

From January of 1995 to December of 2018, a total of 25 children with MHC class II deficiency underwent first HCT at Great North Children’s hospital, Newcastle upon Tyne, United Kingdom. The diagnosis of MHC class II deficiency was confirmed by the absence of DR expression on monocytes, B lymphocytes, and T lymphocytes. The clinical and laboratory data were retrieved from the transplantation database, patients’ medical files, and laboratory records. Long-term follow-up outcomes from overseas patients were collected from the respective referral hospitals. Written informed consent was obtained from the parents or legal guardians of the patients, as per the institutional practice for HCT.

Donor selection, stem cell source, conditioning regimen, and GvHD prophylaxis

The donor selection hierarchy was as follows: (1) matched family donor (MFD), (2) matched unrelated donor (MUD), (3) single-antigen mismatched unrelated donor (MMUD), (4) haploidentical donor (HID). For unrelated donor (UD) grafts, donor-recipient matching was by allele-level typing at HLA-A, HLA-B, HLA-C, HLA-DQ and HLA-DR. Prior to 2009, the conditioning regimen was busulfan or treosulfan in combination with cyclophosphamide with or without serotherapy. From 2009, the conditioning regimen was switched to a myeloablative reduced toxicity conditioning (RTC) regimen using fludarabine, treosulfan, and alemtuzumab for MFDs and MUDs, whereas fludarabine, treosulfan, thiotepa, anti-thymocyte globulin (ATG; Grafalon), and rituximab were used for TCRαβ/CD19-depleted parental grafts. Marrow was the conventional preferred stem cell source, but peripheral blood stem cells (PBSCs) were preferred for patients who received RTC with matched donors or TCRαβ/CD19-depleted parental grafts. Before 2008, GvHD prophylaxis regimens varied but consisted primarily of cyclosporine A (CSA) alone or in combination with methotrexate (MTX). From 2008, GvHD prophylaxis shifted almost exclusively to CSA and mycophenolate mofetil (MMF). From 2017, the recipients of TCRαβ/CD19-depleted parental grafts did not receive any posttransplant GvHD prophylaxis.

Supportive care

Prior to transplant, bronchoalveolar lavage samples from all patients were screened by polymerase chain reaction for viremia, gut viruses, and respiratory viruses. Surveillance for cytomegalovirus (CMV), adenovirus, Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6) viremia, and respiratory and gut viruses was performed weekly since 2000. All patients received antimicrobial prophylaxis against fungi, Pneumocystis jirovecii pneumonia (PCP), and human herpesvirus reactivation. All patients received immunoglobulin (Ig) replacement until normal IgM was made. Donor hematopoietic chimerism was monitored by molecular techniques.

Definition and end points

The main outcomes of interest were overall survival (OS) and event-free survival (EFS). OS was defined as survival from first HCT to last follow-up or death. An event was defined as death, graft failure, or second procedure for slipping chimerism. Other end points assessed were as follows: time to neutrophil recovery (first day of achieving a neutrophil count ≥0.5 × 109/L for 3 consecutive days); time to platelet recovery (platelets >20 × 109/L without transfusions for 7 days); transplant-related complications, as defined and graded according to existing institutional guidelines at the time of HSCT, including infections, hepatic veno-occlusive disease, and GvHD; degree of donor hematopoietic chimerism at the most recent assessment; and immune reconstitution.

Statistical analysis

Quantitative variables are described using median and range, whereas categorical variables are reported with counts and percentages. The χ2 test was used to compare categorical variables. Probabilities of OS and EFS were calculated using the Kaplan-Meier estimate. The log-rank test was used to compare predictors on OS. Variables analyzed included age at transplant, year of transplant (1995-2008 vs 2009-2018), donor type, stem cell source, and stem cell dose. For immune reconstitution kinetics for the first 12 months and the latest lymphocyte subset results, a nested matched case-control study was performed in which each MHC class II–deficient patient was matched with 2 disease controls for the following variables: age (difference <2 years at transplant for immune reconstitution kinetics and at last review for latest lymphocyte subset), donor type, stem cell source, conditioning regimen, serotherapy, GvHD prophylaxis, and CMV reactivation. Disease controls (n = 36) were patients who were transplanted for alternative PID diagnoses: SCID (n = 10), CD40 ligand deficiency (n = 2), Wiskott-Aldrich syndrome (n = 7), chronic granulomatous disease (n = 13) and other PIDs (n = 4; 1 natural killer [NK] deficiency, 1 inducible costimulator deficiency, 1 hemophagocytic lymphohistiocytosis, 1 combined immunodeficiency). Lymphocyte subset at last review was available for 14 of 19 survivors (1 was on active treatment for GvHD, 1 was <1 year post-HCT at the time of analysis, and 3 overseas patients were not able to be contacted). Multilevel mixed-effects modeling was performed for the longitudinal analysis of CD3+, CD4+, CD8+, CD19+, and NK cells, as well as HLA-DR. The Wilcoxon rank-sum test was used to compare latest lymphocyte subsets between patients and disease controls, as above. All quoted P values are 2-sided, with a level of significance of .05. Statistical analyses were performed using STATA 14.2.

Results

Patient characteristics

Patient clinical and immunological features at presentation are shown in Tables 1 and 2. The median age at diagnosis was 6.5 months (range, at birth to 7.5 years). Immunological evaluation performed at referral showed that 14 (56%) had lymphocytopenia, 10 (40%) had normal lymphocyte counts, and 1 had lymphocytosis. CD4+ lymphocytopenia was present in 19 patients (76%), and 6 (24%) had a normal CD4+ lymphocyte count. Six (24%) had CD19 lymphocytopenia. All but 4 patients who were diagnosed at birth had multiple infections. Ten (40%) had a history of PCP, 13 (53%) had viral enteropathy, and 14 (56%) had growth failure at transplant. Two patients had autoimmune phenomena (1 polyarticular juvenile idiopathic arthritis [JIA]; 1 probable autoimmune hepatitis). Two siblings were affected by macrophage activation syndrome (MAS) prior to transplant (patients 8 and 9). Patient 8 was diagnosed with polyarticular JIA at 14 months of age and treated with etanercept, infliximab, MTX, and local and systemic steroids. The diagnosis of MHC class II deficiency was made following immunological evaluation for prolonged fever at 7 years of age. Three months prior to HCT, she developed MAS with persistent fever, cytopenia, high serum ferritin (highest, 38 348 μg/L), elevated triglycerides, and low fibrinogen. She responded to steroid and CSA. There were no clinical features and no laboratory evidence of MAS reactivation during HCT. Patient 9 was diagnosed at 22 months of age after the diagnosis of MHC class II deficiency was made in patient 8. Patient 9 had chronic diarrhea since birth but did not have history of JIA. Similarly, patient 9 developed MAS while waiting for HCT; she responded well to steroid and CSA. Three patients (patients 15, 19, and 21) had novel homozygous RFXANK mutation c.477C>A (p.Ser159Arg), and patient 7 had novel homozygous CIITA mutation c.3003C>G (p.D1001E).

Table 1.

Genetics and immunological features at diagnosis (N = 25)

No/year of HCTCountry of origin (ethnicity)Age at dx, moGeneticsLymphocyte subset (cells/μL) at presentation/prior to HCT (abnormal result according to age-based reference range)DR expression (%)Ig (g/L)Autoantibodies*
LympCD3CD19CD56CD4CD8CD4/CD8 ratioTotal naive T cellsCD27+IgMIgD (%)TBMGAM
1/1995 England (Pakistan) 4.9 Homozygous CIITA mutation 5 796 4 750 640 460 640 (↓) 4 120 (↑) 0.15 (↓) ND ND 1.64 0.11 1.76 ND 
2/1997 England (Pakistan) At birth Homozygous CIITA mutation 4 200 1 905 368 (↓) 368 500 (↓) 1 395 0.35 (↓) ND ND 6.16 0.02 0.18 ND 
3/1997 England (Bangladesh) 4.0 Homozygous CIITA mutation 1 950 (↓) 858 (↓) 839 215 332 (↓) 585 0.57 (↓) ND ND 0.77 <0.13 0.08 ND 
4/2003 England (Pakistan) 4.7 Homozygous RFX5 c.1198C>T (p.R400X) 2 876 (↓) 1 409 (↓) 1167 252 249 (↓) 1 109 0.22 (↓) 73 ND 0.76 <0.07 0.10 ND 
5/2008 Scotland 8.4 Compound heterozygous CIITA mutation c. 2582T>A (p.L861Q); c.2888+1G>A 1 856 (↓) 1 194 (↓) 400 (↓) 139 135 (↓) 1 030 0.13 (↓) ND ND ND 
6/2008 England 15.3 Homozygous RFX5 c.1198G>T (p.E413X) 20 838 (↑) 17 780 (↑) 2253 805 1259 14 434 (↑) 0.09 (↓) 711 ND 1.6 <0.07 <1.1 ND 
7/2011 England 7.8 Homozygous CIITA mutation§ c.3003C>G (p.D1001E) 952 (↓) 331 (↓) 443 (↓) 164 106 (↓) 222 (↓) 0.48 (↓) 162 <1 2.3 0.53 0.96 ND 
8/2012 Scotland (Pakistan) 89.9 Homozygous CIITA mutation c.1595T>C (p.532P) 5 446 3851 956 611 519 (↓) 3 203 (↑) 0.16 (↓) 616 14.9 <0.04 1.30 Negative 
9/2012 Scotland (Pakistan) 22.7 Homozygous CIITA mutation c.1595T>C (p.L532P) 8 066 4 478 3009 425 989 3 520 (↑) 0.28 (↓) 1165 <1 NA NA NA Negative 
10/2015 Saudi Arabia 8.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 2 842 (↓) 1 402 1056 329 777 (↓) 553 1.40 686 <1.0 ND 
112015 Saudi Arabia 6.0 Homozygous RFAXNK mutation c.362A>T (p.R121V) 2 988 (↓) 1 059 1163 685 453 (↓) 209 (↓) 2.17 ND ND 2.3 ND 
12/2015 Saudi Arabia 7.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 6 011 1 987 3563 382 1581 300 (↓) 5.27 596 <1.0 0.05 0.18 ND 
13/2015 Saudi Arabia 6.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 161 1 015 1621 436 695 (↓) 209 3.32 233 NA NA NA ND 
14/2015 Saudi Arabia 6.4 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 361 1 474 1529 304 1097 277 3.96 575 <3.2 0.43 <0.25 Negative 
15/2016 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 6 939 5 963 (↑) 722 217 1077 4 009 (↑) 0.27 (↓) 358 NA NA NA ND 
16/2016 Kuwait At birth Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 5 679 4 327 939 311 3126 1 106 2.83 2652 NA NA NA ND 
17/2017 Saudi Arabia 17.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 1 126 (↓) 744 (↓) 198 (↓) 172 265 (↓) 390 0.68 (↓) ND ND NA NA NA ND 
18/2017 Saudi Arabia 6.0 Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 1 004 (↓) 755 (↓) 123 (↓) 106 374 (↓) 445 0.84 (↓) NA NA NA ND 
19/2017 Saudi Arabia 13.3 Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1 928 (↓) 1 555 323 32 (↓) 378 (↓) 648 0.58 (↓) 218 <1 NA NA NA ND 
20/2017 Kuwait 4.6 Homozygous RFXANK mutation c.271+1delGinsTCAC 2 615 (↓) 1 551 (↓) 797 227 849 (↓) 530 1.60 ND ND 0.66 0.07 0.3 ND 
21/2017 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1 196 (↓) 483 (↓) 603 94 (↓) 158 (↓) 266 (↓) 0.59 (↓) ND ND NA NA NA ND 
22/2017 Saudi Arabia Homozygous RFXANK mutation c.271+1G>TCAC (IVS4+1G>TCAC) 1 761 (↓) 1 372 365 12 (↓) 509 (↓) 684 0.74 (↓) ND ND NA NA NA ND 
23/2018 Saudi Arabia Homozygous RFXANK mutation c.362A>T (p.D121V) 2 010 (↓) 850 (↓) 971 151 414 (↓) 322 (↓) 1.28 206 NA NA NA ND 
24/2018 Saudi Arabia 60 Homozygous RFAXNK mutation c.362A>T (p.R121V) 918 (↓) 626 (↓) 193 (↓) 87 (↓) 190 (↓) 292 (↓) 0.65 (↓) ND ND 0.3 0.25 0.17 ND 
25/2018 Bulgaria Homozygous RFXANK mutation p.R78*C>T 4 246 2 287 1530 388 759 (↓) 1 311 0.58 (↓) 297 ND 3.8 0.08 0.26 ND 
No/year of HCTCountry of origin (ethnicity)Age at dx, moGeneticsLymphocyte subset (cells/μL) at presentation/prior to HCT (abnormal result according to age-based reference range)DR expression (%)Ig (g/L)Autoantibodies*
LympCD3CD19CD56CD4CD8CD4/CD8 ratioTotal naive T cellsCD27+IgMIgD (%)TBMGAM
1/1995 England (Pakistan) 4.9 Homozygous CIITA mutation 5 796 4 750 640 460 640 (↓) 4 120 (↑) 0.15 (↓) ND ND 1.64 0.11 1.76 ND 
2/1997 England (Pakistan) At birth Homozygous CIITA mutation 4 200 1 905 368 (↓) 368 500 (↓) 1 395 0.35 (↓) ND ND 6.16 0.02 0.18 ND 
3/1997 England (Bangladesh) 4.0 Homozygous CIITA mutation 1 950 (↓) 858 (↓) 839 215 332 (↓) 585 0.57 (↓) ND ND 0.77 <0.13 0.08 ND 
4/2003 England (Pakistan) 4.7 Homozygous RFX5 c.1198C>T (p.R400X) 2 876 (↓) 1 409 (↓) 1167 252 249 (↓) 1 109 0.22 (↓) 73 ND 0.76 <0.07 0.10 ND 
5/2008 Scotland 8.4 Compound heterozygous CIITA mutation c. 2582T>A (p.L861Q); c.2888+1G>A 1 856 (↓) 1 194 (↓) 400 (↓) 139 135 (↓) 1 030 0.13 (↓) ND ND ND 
6/2008 England 15.3 Homozygous RFX5 c.1198G>T (p.E413X) 20 838 (↑) 17 780 (↑) 2253 805 1259 14 434 (↑) 0.09 (↓) 711 ND 1.6 <0.07 <1.1 ND 
7/2011 England 7.8 Homozygous CIITA mutation§ c.3003C>G (p.D1001E) 952 (↓) 331 (↓) 443 (↓) 164 106 (↓) 222 (↓) 0.48 (↓) 162 <1 2.3 0.53 0.96 ND 
8/2012 Scotland (Pakistan) 89.9 Homozygous CIITA mutation c.1595T>C (p.532P) 5 446 3851 956 611 519 (↓) 3 203 (↑) 0.16 (↓) 616 14.9 <0.04 1.30 Negative 
9/2012 Scotland (Pakistan) 22.7 Homozygous CIITA mutation c.1595T>C (p.L532P) 8 066 4 478 3009 425 989 3 520 (↑) 0.28 (↓) 1165 <1 NA NA NA Negative 
10/2015 Saudi Arabia 8.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 2 842 (↓) 1 402 1056 329 777 (↓) 553 1.40 686 <1.0 ND 
112015 Saudi Arabia 6.0 Homozygous RFAXNK mutation c.362A>T (p.R121V) 2 988 (↓) 1 059 1163 685 453 (↓) 209 (↓) 2.17 ND ND 2.3 ND 
12/2015 Saudi Arabia 7.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 6 011 1 987 3563 382 1581 300 (↓) 5.27 596 <1.0 0.05 0.18 ND 
13/2015 Saudi Arabia 6.6 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 161 1 015 1621 436 695 (↓) 209 3.32 233 NA NA NA ND 
14/2015 Saudi Arabia 6.4 Homozygous RFAXNK mutation c.362A>T (p.R121V) 3 361 1 474 1529 304 1097 277 3.96 575 <3.2 0.43 <0.25 Negative 
15/2016 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 6 939 5 963 (↑) 722 217 1077 4 009 (↑) 0.27 (↓) 358 NA NA NA ND 
16/2016 Kuwait At birth Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 5 679 4 327 939 311 3126 1 106 2.83 2652 NA NA NA ND 
17/2017 Saudi Arabia 17.0 Homozygous RFXANK mutation c.362A>T (p.D121V) 1 126 (↓) 744 (↓) 198 (↓) 172 265 (↓) 390 0.68 (↓) ND ND NA NA NA ND 
18/2017 Saudi Arabia 6.0 Homozygous RFXANK mutation c.271+1G>C (IVS4+1G>c) 1 004 (↓) 755 (↓) 123 (↓) 106 374 (↓) 445 0.84 (↓) NA NA NA ND 
19/2017 Saudi Arabia 13.3 Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1 928 (↓) 1 555 323 32 (↓) 378 (↓) 648 0.58 (↓) 218 <1 NA NA NA ND 
20/2017 Kuwait 4.6 Homozygous RFXANK mutation c.271+1delGinsTCAC 2 615 (↓) 1 551 (↓) 797 227 849 (↓) 530 1.60 ND ND 0.66 0.07 0.3 ND 
21/2017 Saudi Arabia At birth Homozygous RFXANK mutation§ c.477C>A (p.S159R) 1 196 (↓) 483 (↓) 603 94 (↓) 158 (↓) 266 (↓) 0.59 (↓) ND ND NA NA NA ND 
22/2017 Saudi Arabia Homozygous RFXANK mutation c.271+1G>TCAC (IVS4+1G>TCAC) 1 761 (↓) 1 372 365 12 (↓) 509 (↓) 684 0.74 (↓) ND ND NA NA NA ND 
23/2018 Saudi Arabia Homozygous RFXANK mutation c.362A>T (p.D121V) 2 010 (↓) 850 (↓) 971 151 414 (↓) 322 (↓) 1.28 206 NA NA NA ND 
24/2018 Saudi Arabia 60 Homozygous RFAXNK mutation c.362A>T (p.R121V) 918 (↓) 626 (↓) 193 (↓) 87 (↓) 190 (↓) 292 (↓) 0.65 (↓) ND ND 0.3 0.25 0.17 ND 
25/2018 Bulgaria Homozygous RFXANK mutation p.R78*C>T 4 246 2 287 1530 388 759 (↓) 1 311 0.58 (↓) 297 ND 3.8 0.08 0.26 ND 

B, B cells; dx, diagnosis; Lymp, lymphocytes; M, monocytes; NA, not available; ND, not done; T, T cells. ↑, higher than normal reference range for age; ↓, lower than normal referance range for age.

*

Autoantibodies: antinuclear antibody, double-stranded DNA, rheumatoid factor, antigastric parietal cell antibody, antimitochondrial antibody, antismooth muscle antibody, centromere antibody, tissue transglutaminase antibody, extractable nuclear antigen (ENA) nuclear ribonucleoprotein (RNP) anti-Smith antibody (Sm), anti-Ro antibody, anti-La antibody, Scl-70 antibody, Jo-1 antibody.

Siblings: 1 and 2; 12 and 13; 19 and 21.

§

IgG level was tested on day 12 of life (normal level due to maternal transplacental IgG transfer).

Novel variant.

Table 2.

Detailed patient and transplant characteristics (N = 25)

No./year of HCTAge at dx, moAge at HCT, moInterval between dx and HCT, moPretransplant infections and medical issuesDonorStem cell sourceConditioning and GvHD prophylaxisAcute GvHDSignificant complications during and after HCTOutcome
1/1995 4.9 7.0 2.1 Disseminated CMV infection (blood, liver, stools, NPS, urine). MFD (paternal uncle) BM Oral Bu 16 mg/kg (Bu AUC 1837 μmol × min). None Pneumonitis required mechanical ventilation. Died of CMV pneumonitis (postmortem) at day +17. 
Poliovirus and rotavirus (stools). Cy 200 mg/kg. AKI, seizures, toxic epidermal necrolysis (skin biopsy proven). 
Haemophilus influenzae (NPS). Maternal T-cell engraftment (skin biopsy proven). Alemtuzumab 1 mg/kg. 
CSA. 
2/1997 At birth 0.9 0.8 Staphylococcus aureus septicemia. MFD (great-granduncle) BM Oral Bu 16 mg/kg (no Bu pK). None Engraftment pneumonitis required mechanical ventilation and responded IST (treated with neb budesonide, neb Ig, systemic steroid, ATG, anti-TNF monoclonal antibody). Secondary autologous reconstitution at day +76. 
Cy 200 mg/kg. Rabbit ATG 2.2 mg/kg. Severe hypertension with seizures. Second HCT using a different 7/8 MMFD at 5.6 mo of age. 
CSA/MTX. CMV viremia. Staphylococcus epidermidis bacteremia. Died of interstitial pneumonitis at day +88 postsecond HCT. 
Diagnosed as pyloric stenosis at day +56 and underwent pyloromyotomy on day +69. 
3/1997 4.0 5.8 1.8 PCP (BAL). MSD BM Oral Bu 16 mg/kg (no Bu pK). None Worsening pretransplant respiratory dysfunction from day +9 and required mechanical ventilation from day +17. Died of parainfluenza virus 3 pneumonitis at day +19. 
Candida perianal ulcers. Cy 200 mg/kg. NPS was positive for parainfluenza virus 3 and rhinovirus. 
Congenital retinal dystrophy. No serotherapy. Treated with neb budesonide, neb IVIg, systemic steroid, ATG, and neb and IV ribavirin. 
CSA/MTX. 
4/2003 4.7 6.2 1.5 PCP (BAL). 7/8 MMUD CB Flu 150 mg/m2. Melph 140 mg/m2. Alemtuzumab 1 mg/kg. None Staphylococcus epidermidis bacteremia. Alive 
Fungal (hyphae on BAL). CSA/steroid. CMV pneumonitis rotavirus. 
Poliovirus (gut and NPS). 
5/2008 8.4 11.3 2.9 PCP (BAL). MFD BM Treo 36 mg/m2Grade 1 skin Pneumonitis. Cryopreserved marrow top-up at day +54 for slipping chimerism. 
Norovirus type 2 enteropathy. Cy 200 mg/kg. Capillary leakage syndrome. Second conditioned HCT using the same donor at day +186. 
HHV6 viremia. No serotherapy. CSA/MMF. Diagnosed to have pelvic ureteric junction obstruction at 2 y of age following urosepsis. Died of urosepsis 3.8 y postsecond HCT. 
Maternal T-cell engraftment. Had stenting done. 
Seizure with neurodevelopmental delay and absent corpus collusum. Had sterile liver nodules 2.8 y of age. 
Operated gut malrotation. Required ventricular peritoneal shunt at 3 y of age. 
6/2008 15.3 17.7 2.4 CMV (NPS). MSD BM Treo 42 mg/m2Grade 1 skin CMV viremia. Died of pneumonitis with multiorgan failure at day +261. 
Norovirus type 2 enteropathy. RSV and parainfluenza virus 3 (NPS). Cy 200 mg/kg. Adenovirus (stools). Post mortem examination revealed positive HHV6 in lung and liver. 
Probable autoimmune hepatitis (isolated raised hepatic transaminases). No serotherapy. CSA/MMF. Developed respiratory failure required mechanical ventilation at 8 mo post-HCT. 
7/2011 7.8 9.8 2.0 PCP. MRD PBSC Treo 36 g/m2Grade 1 skin Engraftment pneumonitis (treated with neb budesonide). Alive 
Chronic diarrhea (normal gut biopsy and negative pathogens). Flu 150 mg/m2
Alemtuzumab 1 mg/kg. 
CSA/MMF. 
8*/2012 89.9 93.3 3.5 Polyarticular juvenile idiopathic arthritis since 14 mo of age, treated with steroid, etanercept and infliximab. MUD PBSC Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stools, and NPS). Alive 
Macrophage-activating syndrome at 7 y of age, treated with steroid and CSA. Mycobacterium avium-M. intracellulare (sputum and BAL). Flu 150 mg/m2CMV viremia. 
H. influenzae (BAL). Alemtuzumab 1 mg/kg. Micrococcus luteus bacteremia. 
CMV (BAL). CSA/MMF. 
HHV7 (blood). 
Norovirus and sapovirus (stools). 
Right middle lobe bronchiectasis. 
9*/2012 22.7 27.4 4.8 Macrophage-activating syndrome at 2 y old, treated with steroid and CSA. 9/10 A-MMUD PBSCs Treo 42 g/m2Grade 2 skin Disseminated adenovirus (blood, gut, NPS). Alive 
Bronchiectasis. Flu 150 mg/m2CMV viremia. 
Norovirus enteropathy. Alemtuzumab 1 mg/kg. 
CMV (BAL). CSA/MMF 
10/2015 8.0 16.2 8.2 PCP. 9/10 C-MMUD BM Treo 42 g/m2Grade 1 skin S. epidermidis bacteremia. Alive 
H. influenzae (BAL). Flu 150 mg/m2Immune reconstitution . abscess at day +141. 
Pseudomonas aeruginosa (BAL). Alemtuzumab 1 mg/kg. 
CSA/MMF 
11/2015 6.0 29.4 23.4 Diagnosed at 6 mo because older sibling died at 6 y. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2Grade 2 skin Disseminated adenovirus (blood, stool, NPS); received adenovirus CTL. Alive 
Disseminated adenovirus (BAL, blood stools). Flu 150 mg/m2HHV6 viremia. 
Multiple gut viruses (norovirus and adenovirus). Thio 10 mg/kg. Parainfluenza virus 1. 
ATG 15 mg/kg. Escherichia coli urinary tract infection. 
RTX 200 mg/mg. 
CSA. 
12*/2015 7.6 15.7 8.1 Enterovirus hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2Grade 2 skin None Alive 
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). Flu 150 mg/m2Stopped PN at day +135 post-HCT. 
Streptococcus oralis bacteremia. Alemtuzumab 1 mg/kg. 
CSA/MMF. 
13*/2015 6.6 16.4 9.8 PCP. Enterovirus viremia and hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2Grade 1 skin None Alive 
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). E. coli and alpha hemolytic Streptococcus bacteremia. Flu 150 mg/m2Stopped PN at day +110 post-HCT. 
Alemtuzumab 1 mg/kg. 
CSA/MMF. 
14/2015 6.5 21.4 14.9 PCP. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2None Enterovirus meningitis with communicating hydrocephalus on day +56. Alive 
Multiple gut viruses (norovirus, enterovirus). Flu 150 mg/m2
Thio 10 mg/kg. 
RTX 200 mg/m2
ATG 15 mg/kg. 
CSA. 
15/2016 At birth 47.7 47.7 CMV viremia. MUD PBSCs Treo 42 g/m2None Disseminated adenovirus (blood, eye swab). Alive 
Disseminated parechovirus (blood, stool). Flu 150 mg/m2CMV viremia. 
Sapovirus (stool). Alemtuzumab 1 mg/kg. 
Nontuberculous mycobacteria of lung (biopsy proven). CSA/MMF. 
E. coli urinary tract infection. 
Osteopenic fracture of right tibia and fibula. 
16/2016 At birth 9.6 9.6 Parainfluenza virus 3 (BAL). MUD PBSCs Treo 42 g/m2None None Alive 
Streptococcus pneumoniae (BAL). Flu 150 mg/m2
Enterovirus (stool). Alemtuzumab 1 mg/kg. 
CSA/MMF. 
17/2017 17 31 14 Multiple gut viruses (adenovirus, sapovirus, enterovirus, norovirus). Maternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin Disseminated adenovirus with pericardial effusion requiring pericardial window. Alive 
Multiple respiratory viruses (parainfluenza virus 3, adenovirus, RSV). Add-back T cells. Flu 150 mg/m2
HHV6 viremia. Thio 10 mg/kg. 
S. pneumoniae (BAL). RTX 200 mg/m2
ATG 15 mg/kg. 
No GvHD prophylaxis. 
18/2017 60.7 54.7 PCP. Paternal HID TCRαβ/CD19-depleted PBSC. Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stool, NPS). Alive 
Severe malnutrition. Add-back T cells. Flu 150 mg/m2Stopped PN at day +67 post-HCT. 
PN-dependent enteropathy with multiple gut viruses (norovirus, adenovirus, enterovirus). Thio 10 mg/kg. 
HHV6 viremia. RTX 200 mg/m2
Norovirus and adenovirus enteropathy. ATG 15 mg/kg. 
Presumed fungal splenic abscess. No GvHD prophylaxis. 
Multiple osteopenic fractures secondary to vitamin D deficiency. 
19*/2017 13.2 81.7 68.4 PCP. MUD PBSCs Treo 42 g/m2None Disseminated adenovirus (blood, stool, NPS). Alive 
Norovirus (gut). Flu 150 mg/m2
HHV6 viremia. Alemtuzumab 1 mg/kg. 
20/2017 4.6 12.3 7.7 HHV 6 (blood and CSF). Adenovirus (blood and stool). Coxsackievirus A type 6 (stool, NPS). Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stool). Alive 
Norovirus (stool). Flu 150 mg/m2HHV6 viremia. 
RSV and parainfluenza virus 2 and 3 on NPS. Thio 10 mg/kg. Encephalopathy of unknown etiology (normal CSF and MRI brain). 
RTX 200 mg/m2. ATG 15 mg/kg. Full neurological recovery. 
No GvHD prophylaxis. 
21*/2017 At birth 62.7 62.7 Severe malnutrition. MUD PBSCs Treo 42 g/m2None HHV6 viremia. Alive 
PN-dependent enteropathy with multiple gut viruses (norovirus, parechovirus). Flu 150 mg/m2Stopped PN at day +59 post-HCT. 
Parainfluenza virus 4. Alemtuzumab 1 mg/kg. 
HHV6 viremia. CSA/MMF. 
22/2017 24 73.6 49.6 Severe malnutrition. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin PN-dependent gut failure. Received second HCT for secondary aplasia. 
Disseminated adenovirus (blood, BAL, stools). Add-back T cells. Flu 150 mg/m2Disseminated adenovirus. Died of cerebral hemorrhage postsecond HCT. 
Disseminated CMV (blood, BAL). Thio 10 mg/kg. RSV pneumonia. 
EBV in BAL. RTX 200 mg/m2HHV6 viremia. 
HHV6 viremia. ATG 15 mg/kg. 
RSV (NPS). No GvHD prophylaxis. 
Multiple gut viruses (adenovirus, enterovirus, sapovirus, astrovirus, norovirus). 
23/2018 6.0 22.2 16.7 HHV6 viremia. MUD PBSCs Treo 42 g/m2None HHV6 viremia. Alive 
Norovirus (stool). Flu 150 mg/m2
RSV and parainfluenza virus 1 (NPS). Alemtuzumab 1 mg/kg. 
 CSA/MMF. 
24/2018 5.0 78.8 73.8 PCP. 9/10 A-MMUD PBSCs Treo 42 g/m2Grade 2 skin HHV6 viremia. Alive 
RSV pneumonia. Flu 150 mg/m2PN-dependent viral enteropathy on gut biopsy; no evidence of gut GvHD on gut biopsy. Stopped PN at day +641 post-HCT. 
PN-dependent enteropathy with multiple gut viruses (adenovirus, norovirus, astrovirus). Alemtuzumab 1 mg/kg. Slow immune reconstitution secondary steroid-dependent skin acute GvHD. 
Candida esophagitis. CSA/MMF.  
Disseminated BCG at 3 y of age.   
25/2018 6.0 22.8 16.8 PCP. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2Grade 2 skin None Alive 
Chronic diarrhea (Salmonella spp. and norovirus). Flu 150 mg/m2
Thio 10 mg/kg. 
RTX 200 mg/m2
ATG 15 mg/kg. 
No GvHD prophylaxis. 
No./year of HCTAge at dx, moAge at HCT, moInterval between dx and HCT, moPretransplant infections and medical issuesDonorStem cell sourceConditioning and GvHD prophylaxisAcute GvHDSignificant complications during and after HCTOutcome
1/1995 4.9 7.0 2.1 Disseminated CMV infection (blood, liver, stools, NPS, urine). MFD (paternal uncle) BM Oral Bu 16 mg/kg (Bu AUC 1837 μmol × min). None Pneumonitis required mechanical ventilation. Died of CMV pneumonitis (postmortem) at day +17. 
Poliovirus and rotavirus (stools). Cy 200 mg/kg. AKI, seizures, toxic epidermal necrolysis (skin biopsy proven). 
Haemophilus influenzae (NPS). Maternal T-cell engraftment (skin biopsy proven). Alemtuzumab 1 mg/kg. 
CSA. 
2/1997 At birth 0.9 0.8 Staphylococcus aureus septicemia. MFD (great-granduncle) BM Oral Bu 16 mg/kg (no Bu pK). None Engraftment pneumonitis required mechanical ventilation and responded IST (treated with neb budesonide, neb Ig, systemic steroid, ATG, anti-TNF monoclonal antibody). Secondary autologous reconstitution at day +76. 
Cy 200 mg/kg. Rabbit ATG 2.2 mg/kg. Severe hypertension with seizures. Second HCT using a different 7/8 MMFD at 5.6 mo of age. 
CSA/MTX. CMV viremia. Staphylococcus epidermidis bacteremia. Died of interstitial pneumonitis at day +88 postsecond HCT. 
Diagnosed as pyloric stenosis at day +56 and underwent pyloromyotomy on day +69. 
3/1997 4.0 5.8 1.8 PCP (BAL). MSD BM Oral Bu 16 mg/kg (no Bu pK). None Worsening pretransplant respiratory dysfunction from day +9 and required mechanical ventilation from day +17. Died of parainfluenza virus 3 pneumonitis at day +19. 
Candida perianal ulcers. Cy 200 mg/kg. NPS was positive for parainfluenza virus 3 and rhinovirus. 
Congenital retinal dystrophy. No serotherapy. Treated with neb budesonide, neb IVIg, systemic steroid, ATG, and neb and IV ribavirin. 
CSA/MTX. 
4/2003 4.7 6.2 1.5 PCP (BAL). 7/8 MMUD CB Flu 150 mg/m2. Melph 140 mg/m2. Alemtuzumab 1 mg/kg. None Staphylococcus epidermidis bacteremia. Alive 
Fungal (hyphae on BAL). CSA/steroid. CMV pneumonitis rotavirus. 
Poliovirus (gut and NPS). 
5/2008 8.4 11.3 2.9 PCP (BAL). MFD BM Treo 36 mg/m2Grade 1 skin Pneumonitis. Cryopreserved marrow top-up at day +54 for slipping chimerism. 
Norovirus type 2 enteropathy. Cy 200 mg/kg. Capillary leakage syndrome. Second conditioned HCT using the same donor at day +186. 
HHV6 viremia. No serotherapy. CSA/MMF. Diagnosed to have pelvic ureteric junction obstruction at 2 y of age following urosepsis. Died of urosepsis 3.8 y postsecond HCT. 
Maternal T-cell engraftment. Had stenting done. 
Seizure with neurodevelopmental delay and absent corpus collusum. Had sterile liver nodules 2.8 y of age. 
Operated gut malrotation. Required ventricular peritoneal shunt at 3 y of age. 
6/2008 15.3 17.7 2.4 CMV (NPS). MSD BM Treo 42 mg/m2Grade 1 skin CMV viremia. Died of pneumonitis with multiorgan failure at day +261. 
Norovirus type 2 enteropathy. RSV and parainfluenza virus 3 (NPS). Cy 200 mg/kg. Adenovirus (stools). Post mortem examination revealed positive HHV6 in lung and liver. 
Probable autoimmune hepatitis (isolated raised hepatic transaminases). No serotherapy. CSA/MMF. Developed respiratory failure required mechanical ventilation at 8 mo post-HCT. 
7/2011 7.8 9.8 2.0 PCP. MRD PBSC Treo 36 g/m2Grade 1 skin Engraftment pneumonitis (treated with neb budesonide). Alive 
Chronic diarrhea (normal gut biopsy and negative pathogens). Flu 150 mg/m2
Alemtuzumab 1 mg/kg. 
CSA/MMF. 
8*/2012 89.9 93.3 3.5 Polyarticular juvenile idiopathic arthritis since 14 mo of age, treated with steroid, etanercept and infliximab. MUD PBSC Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stools, and NPS). Alive 
Macrophage-activating syndrome at 7 y of age, treated with steroid and CSA. Mycobacterium avium-M. intracellulare (sputum and BAL). Flu 150 mg/m2CMV viremia. 
H. influenzae (BAL). Alemtuzumab 1 mg/kg. Micrococcus luteus bacteremia. 
CMV (BAL). CSA/MMF. 
HHV7 (blood). 
Norovirus and sapovirus (stools). 
Right middle lobe bronchiectasis. 
9*/2012 22.7 27.4 4.8 Macrophage-activating syndrome at 2 y old, treated with steroid and CSA. 9/10 A-MMUD PBSCs Treo 42 g/m2Grade 2 skin Disseminated adenovirus (blood, gut, NPS). Alive 
Bronchiectasis. Flu 150 mg/m2CMV viremia. 
Norovirus enteropathy. Alemtuzumab 1 mg/kg. 
CMV (BAL). CSA/MMF 
10/2015 8.0 16.2 8.2 PCP. 9/10 C-MMUD BM Treo 42 g/m2Grade 1 skin S. epidermidis bacteremia. Alive 
H. influenzae (BAL). Flu 150 mg/m2Immune reconstitution . abscess at day +141. 
Pseudomonas aeruginosa (BAL). Alemtuzumab 1 mg/kg. 
CSA/MMF 
11/2015 6.0 29.4 23.4 Diagnosed at 6 mo because older sibling died at 6 y. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2Grade 2 skin Disseminated adenovirus (blood, stool, NPS); received adenovirus CTL. Alive 
Disseminated adenovirus (BAL, blood stools). Flu 150 mg/m2HHV6 viremia. 
Multiple gut viruses (norovirus and adenovirus). Thio 10 mg/kg. Parainfluenza virus 1. 
ATG 15 mg/kg. Escherichia coli urinary tract infection. 
RTX 200 mg/mg. 
CSA. 
12*/2015 7.6 15.7 8.1 Enterovirus hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2Grade 2 skin None Alive 
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). Flu 150 mg/m2Stopped PN at day +135 post-HCT. 
Streptococcus oralis bacteremia. Alemtuzumab 1 mg/kg. 
CSA/MMF. 
13*/2015 6.6 16.4 9.8 PCP. Enterovirus viremia and hepatitis (biopsy proven). 9/10 DQ-MMUD PBSCs Treo 42 g/m2Grade 1 skin None Alive 
PN-dependent enteropathy with multiple gut viruses (enterovirus and sapovirus). E. coli and alpha hemolytic Streptococcus bacteremia. Flu 150 mg/m2Stopped PN at day +110 post-HCT. 
Alemtuzumab 1 mg/kg. 
CSA/MMF. 
14/2015 6.5 21.4 14.9 PCP. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2None Enterovirus meningitis with communicating hydrocephalus on day +56. Alive 
Multiple gut viruses (norovirus, enterovirus). Flu 150 mg/m2
Thio 10 mg/kg. 
RTX 200 mg/m2
ATG 15 mg/kg. 
CSA. 
15/2016 At birth 47.7 47.7 CMV viremia. MUD PBSCs Treo 42 g/m2None Disseminated adenovirus (blood, eye swab). Alive 
Disseminated parechovirus (blood, stool). Flu 150 mg/m2CMV viremia. 
Sapovirus (stool). Alemtuzumab 1 mg/kg. 
Nontuberculous mycobacteria of lung (biopsy proven). CSA/MMF. 
E. coli urinary tract infection. 
Osteopenic fracture of right tibia and fibula. 
16/2016 At birth 9.6 9.6 Parainfluenza virus 3 (BAL). MUD PBSCs Treo 42 g/m2None None Alive 
Streptococcus pneumoniae (BAL). Flu 150 mg/m2
Enterovirus (stool). Alemtuzumab 1 mg/kg. 
CSA/MMF. 
17/2017 17 31 14 Multiple gut viruses (adenovirus, sapovirus, enterovirus, norovirus). Maternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin Disseminated adenovirus with pericardial effusion requiring pericardial window. Alive 
Multiple respiratory viruses (parainfluenza virus 3, adenovirus, RSV). Add-back T cells. Flu 150 mg/m2
HHV6 viremia. Thio 10 mg/kg. 
S. pneumoniae (BAL). RTX 200 mg/m2
ATG 15 mg/kg. 
No GvHD prophylaxis. 
18/2017 60.7 54.7 PCP. Paternal HID TCRαβ/CD19-depleted PBSC. Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stool, NPS). Alive 
Severe malnutrition. Add-back T cells. Flu 150 mg/m2Stopped PN at day +67 post-HCT. 
PN-dependent enteropathy with multiple gut viruses (norovirus, adenovirus, enterovirus). Thio 10 mg/kg. 
HHV6 viremia. RTX 200 mg/m2
Norovirus and adenovirus enteropathy. ATG 15 mg/kg. 
Presumed fungal splenic abscess. No GvHD prophylaxis. 
Multiple osteopenic fractures secondary to vitamin D deficiency. 
19*/2017 13.2 81.7 68.4 PCP. MUD PBSCs Treo 42 g/m2None Disseminated adenovirus (blood, stool, NPS). Alive 
Norovirus (gut). Flu 150 mg/m2
HHV6 viremia. Alemtuzumab 1 mg/kg. 
20/2017 4.6 12.3 7.7 HHV 6 (blood and CSF). Adenovirus (blood and stool). Coxsackievirus A type 6 (stool, NPS). Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin Disseminated adenovirus (blood, stool). Alive 
Norovirus (stool). Flu 150 mg/m2HHV6 viremia. 
RSV and parainfluenza virus 2 and 3 on NPS. Thio 10 mg/kg. Encephalopathy of unknown etiology (normal CSF and MRI brain). 
RTX 200 mg/m2. ATG 15 mg/kg. Full neurological recovery. 
No GvHD prophylaxis. 
21*/2017 At birth 62.7 62.7 Severe malnutrition. MUD PBSCs Treo 42 g/m2None HHV6 viremia. Alive 
PN-dependent enteropathy with multiple gut viruses (norovirus, parechovirus). Flu 150 mg/m2Stopped PN at day +59 post-HCT. 
Parainfluenza virus 4. Alemtuzumab 1 mg/kg. 
HHV6 viremia. CSA/MMF. 
22/2017 24 73.6 49.6 Severe malnutrition. Paternal HID TCRαβ/CD19-depleted PBSCs. Treo 42 g/m2Grade 1 skin PN-dependent gut failure. Received second HCT for secondary aplasia. 
Disseminated adenovirus (blood, BAL, stools). Add-back T cells. Flu 150 mg/m2Disseminated adenovirus. Died of cerebral hemorrhage postsecond HCT. 
Disseminated CMV (blood, BAL). Thio 10 mg/kg. RSV pneumonia. 
EBV in BAL. RTX 200 mg/m2HHV6 viremia. 
HHV6 viremia. ATG 15 mg/kg. 
RSV (NPS). No GvHD prophylaxis. 
Multiple gut viruses (adenovirus, enterovirus, sapovirus, astrovirus, norovirus). 
23/2018 6.0 22.2 16.7 HHV6 viremia. MUD PBSCs Treo 42 g/m2None HHV6 viremia. Alive 
Norovirus (stool). Flu 150 mg/m2
RSV and parainfluenza virus 1 (NPS). Alemtuzumab 1 mg/kg. 
 CSA/MMF. 
24/2018 5.0 78.8 73.8 PCP. 9/10 A-MMUD PBSCs Treo 42 g/m2Grade 2 skin HHV6 viremia. Alive 
RSV pneumonia. Flu 150 mg/m2PN-dependent viral enteropathy on gut biopsy; no evidence of gut GvHD on gut biopsy. Stopped PN at day +641 post-HCT. 
PN-dependent enteropathy with multiple gut viruses (adenovirus, norovirus, astrovirus). Alemtuzumab 1 mg/kg. Slow immune reconstitution secondary steroid-dependent skin acute GvHD. 
Candida esophagitis. CSA/MMF.  
Disseminated BCG at 3 y of age.   
25/2018 6.0 22.8 16.8 PCP. Maternal HID TCRαβ/CD19-depleted PBSCs Treo 42 g/m2Grade 2 skin None Alive 
Chronic diarrhea (Salmonella spp. and norovirus). Flu 150 mg/m2
Thio 10 mg/kg. 
RTX 200 mg/m2
ATG 15 mg/kg. 
No GvHD prophylaxis. 

AKI, acute kidney injury; AUC, area under the curve; BAL, bronchoalveolar lavage; BCG, bacille Calmette-Guerin; BM, bone marrow; Bu, busulfan; CB, cord blood; CSF, cerebrospinal fluid; CTL, cytotoxic T cells; Cy, cyclophosphamide; dx, diagnosis; Flu, fludarabine; IST, immunosuppressive therapy; Melph, melphalan; MMFD, mismatched family donor; MRI, magnetic resonance imaging; neb, nebulized; NPS, nasopharyngeal specimen; pK, pharmacokinetics; PN, parenteral nutrition; RSV, respiratory syncytial virus; RTX, rituximab; Thio, thiotepa; Treo, treosulfan; TNF, tumor necrosis factor.

Transplantation characteristics

Transplantation characteristics are summarized in Tables 2 and 3. The median age at transplant was 21.4 months (range, 0.9 months to 7.8 years) and the median interval between diagnosis and transplant was 9.2 months (range, 0.9 months to 6 years). Six (24%) had MFDs, 12 (48%) had UDs, and 7 (28%) had HIDs. Unmanipulated PBSCs were the stem cell source in 10 (40%) patients, and 7 (28%) received TCRαβ/CD19-depleted parental PBSCs. Only 1 patient received a cord blood transplant. Treosulfan-based RTC was used in 84% of patients (n = 21). Twenty-one patients (84%) received alemtuzumab (n = 14) or ATG (n = 8) as serotherapy.

Table 3.

Patient and transplantation characteristics and outcome after HCT in children with MHC class II expression deficiency (N = 25)

VariablesResults
Patient characteristics  
 Year of transplant  
  1998-2007 6 (24) 
  2008-2018 19 (76) 
 Male 15 (60) 
 Age at diagnosis, median (range), mo 6.5 (birth-89.6) 
 Age at transplant, median (range), mo 21.4 (0.9-93.3) 
 Interval between diagnosis and HCT, median (range), mo 9.2 (0.9-71.5) 
 Newborn MHC class II expression deficiency 4 (16) 
 Positive family history 12 (48) 
 Consanguineous parents 22 (88) 
 BCG vaccination 21 (84) 
 History of PCP 10 (40) 
 Pretransplant chronic diarrhea 13 (52) 
 Growth failure at HCT (<9th centile) 14 (56) 
 Pretransplant autoimmune disease 2 (8) 
Donor characteristics  
 Type of donor  
  MFD 6 (24) 
  MUD 6 (24) 
  MMUD* 6 (24) 
  Parental HID 7 (28) 
 Stem cell source  
  Marrow 7 (28) 
  Unmanipulated PB 10 (40) 
  TCRαβ/CD19-depleted PBSCs 7 (28) 
  CB 1 (4) 
Graft details, median (range)  
Marrow  
  TNC, ×108/kg 4.1 (2.5-11.5) 
  CD34, ×106/kg 3.4 (3.1-5.9) 
  CD3, ×108/kg 0.61 (0.37-1.0) 
  CD19, ×107/kg 3.85 (1.6-6.1) 
Unmanipulated PB  
  TNC, ×108/kg 16.8 (13.4-42.7) 
  CD34, ×106/kg 12.5 (6.3-28.6) 
  CD3, ×108/kg 4.95 (3.4-9.6) 
  CD19, ×107/kg 9.6 (1.6-22.0) 
TCRαβ/CD19-depleted PBSCs  
  TNC, ×108/kg 12.7 (7.6-28.0) 
  CD34, ×106/kg 26.1 (6.9-56.6) 
  CD3, ×107/kg 4.2 (1.4-45) 
  CD19, ×105/kg 6.0 (3.6-12.0) 
  TCRαβ, ×104/kg 5.0 (2.7-7.0) 
  NK cells, ×107/kg 5.5 (1.8-11.0) 
Transplant characteristics  
 Conditioning regimen  
  Myeloablative conditioning  
   Busulfan-cyclophosphamide 3 (12) 
   Treosulfan-cyclophosphamide 2 (8) 
   Fludarabine-treosulfan-thiotepa 7 (28) 
RTC  
   Treosulfan-fludarabine 12 (48) 
   Fludarabine-melphalan 1 (4) 
 Serotherapy  
  None 4 (12) 
  ATG 8 (32) 
  Alemtuzumab 14 (56) 
 GvHD prophylaxis  
  None 5 (20) 
  CSA alone 3 (12) 
  CSA + MTX 2 (8) 
  CSA + MMF 14 (56) 
  CSA + steroid (for CB) 1 (4) 
 Hematopoietic recovery  
  Days to neutrophil recovery, median (range) 15 (8-22) 
  Days to platelet recovery, median (range) 16 (11-42) 
 Transplant-related complications  
  Acute GvHD 13 (52) 
  Grade II-IV 4 (16) 
  Grade III-IV 
  Chronic GvHD 
  Veno-occlusive disease 
  CMV viremia 7 (28) 
  Adenoviremia 9 (36) 
  HHV6 viremia 7 (28) 
  EBV viremia 1 (4) 
 Patients who required parenteral nutrition 17 (68) 
 Patients with graft failure 3 (12) 
  Secondary autologous reconstitution 2 (8) 
  Secondary aplasia 1 (4) 
 Cause of death (n = 6)  
  Pneumonitis 4 (16) 
  Cerebral hemorrhage 1 (4) 
  Infection 1 (4) 
VariablesResults
Patient characteristics  
 Year of transplant  
  1998-2007 6 (24) 
  2008-2018 19 (76) 
 Male 15 (60) 
 Age at diagnosis, median (range), mo 6.5 (birth-89.6) 
 Age at transplant, median (range), mo 21.4 (0.9-93.3) 
 Interval between diagnosis and HCT, median (range), mo 9.2 (0.9-71.5) 
 Newborn MHC class II expression deficiency 4 (16) 
 Positive family history 12 (48) 
 Consanguineous parents 22 (88) 
 BCG vaccination 21 (84) 
 History of PCP 10 (40) 
 Pretransplant chronic diarrhea 13 (52) 
 Growth failure at HCT (<9th centile) 14 (56) 
 Pretransplant autoimmune disease 2 (8) 
Donor characteristics  
 Type of donor  
  MFD 6 (24) 
  MUD 6 (24) 
  MMUD* 6 (24) 
  Parental HID 7 (28) 
 Stem cell source  
  Marrow 7 (28) 
  Unmanipulated PB 10 (40) 
  TCRαβ/CD19-depleted PBSCs 7 (28) 
  CB 1 (4) 
Graft details, median (range)  
Marrow  
  TNC, ×108/kg 4.1 (2.5-11.5) 
  CD34, ×106/kg 3.4 (3.1-5.9) 
  CD3, ×108/kg 0.61 (0.37-1.0) 
  CD19, ×107/kg 3.85 (1.6-6.1) 
Unmanipulated PB  
  TNC, ×108/kg 16.8 (13.4-42.7) 
  CD34, ×106/kg 12.5 (6.3-28.6) 
  CD3, ×108/kg 4.95 (3.4-9.6) 
  CD19, ×107/kg 9.6 (1.6-22.0) 
TCRαβ/CD19-depleted PBSCs  
  TNC, ×108/kg 12.7 (7.6-28.0) 
  CD34, ×106/kg 26.1 (6.9-56.6) 
  CD3, ×107/kg 4.2 (1.4-45) 
  CD19, ×105/kg 6.0 (3.6-12.0) 
  TCRαβ, ×104/kg 5.0 (2.7-7.0) 
  NK cells, ×107/kg 5.5 (1.8-11.0) 
Transplant characteristics  
 Conditioning regimen  
  Myeloablative conditioning  
   Busulfan-cyclophosphamide 3 (12) 
   Treosulfan-cyclophosphamide 2 (8) 
   Fludarabine-treosulfan-thiotepa 7 (28) 
RTC  
   Treosulfan-fludarabine 12 (48) 
   Fludarabine-melphalan 1 (4) 
 Serotherapy  
  None 4 (12) 
  ATG 8 (32) 
  Alemtuzumab 14 (56) 
 GvHD prophylaxis  
  None 5 (20) 
  CSA alone 3 (12) 
  CSA + MTX 2 (8) 
  CSA + MMF 14 (56) 
  CSA + steroid (for CB) 1 (4) 
 Hematopoietic recovery  
  Days to neutrophil recovery, median (range) 15 (8-22) 
  Days to platelet recovery, median (range) 16 (11-42) 
 Transplant-related complications  
  Acute GvHD 13 (52) 
  Grade II-IV 4 (16) 
  Grade III-IV 
  Chronic GvHD 
  Veno-occlusive disease 
  CMV viremia 7 (28) 
  Adenoviremia 9 (36) 
  HHV6 viremia 7 (28) 
  EBV viremia 1 (4) 
 Patients who required parenteral nutrition 17 (68) 
 Patients with graft failure 3 (12) 
  Secondary autologous reconstitution 2 (8) 
  Secondary aplasia 1 (4) 
 Cause of death (n = 6)  
  Pneumonitis 4 (16) 
  Cerebral hemorrhage 1 (4) 
  Infection 1 (4) 

Unless otherwise indicated, data are n (%).

BCG, bacille Calmette-Guérin; CB, cord blood; PB, peripheral blood; TNC, total nucleated cell dose.

*

Six patients had a 9/10 MMUD transplant.

Three patients received add-back T cells.

Six patients received ATG (Grafalon) and 1 patient received thymoglobulin.

Engraftment and transplant-related complications

The median times to neutrophil and platelet engraftment were 15 days (range, 8-22) and 16 days (range, 11-42), respectively (Table 3). Thirteen (52%) patients had acute GvHD, of whom 4 (16%) had grade II acute cutaneous GvHD, and none had visceral GvHD. None had grade III-IV acute GvHD or chronic GvHD. All 5 patients who had pretransplant parenteral nutritional–dependent enteropathy were able to establish full enteral nutrition posttransplant. The parenteral nutrition was discontinued at a median of 135 days post-HCT (range, 67-641) in these patients. Sixteen (64%) patients developed new-onset viremia during transplant. Five of 6 deaths were due to transplant-related complications (4 pneumonitis and 1 cerebral hemorrhage). Patient 5 had congenital pelvic ureteric junction obstruction and died of urosepsis after 2 successful MFD transplants and good immune reconstitution.

OS and EFS

The median duration of follow-up of surviving patients was 2.9 years (range, 0.7-7.3). The 3-year OS was 78% (95% CI, 56-91), increasing to 94% (95% CI, 66-99) for children transplanted after 2008 (n = 19) vs 33% (95% CI, 46-68) for the children transplanted between 1995 and 2008 (n = 6; P = .003) (Figure 1A-B). For transplants after 2008, the OS was comparable among MFDs (100%), UDs (100%), and HIDs (83%; 95% CI, 27-97; P = .40) (Figure 1C). Age at transplant (P = .59), stem cell source (P = .50), total nucleated cell dose (P = .59) and CD34 cell dose (P = .59), and stem cell dose were not associated with OS in patients who were transplanted between 2009 and 2018.

Figure 1.

Transplant survival in children with MHC class II deficiency. (A) OS for the entire cohort (n = 25). (B) OS according to years of transplant. (C) OS according to donor type in patients transplanted between 2008 and 2018 (n = 19).

Figure 1.

Transplant survival in children with MHC class II deficiency. (A) OS for the entire cohort (n = 25). (B) OS according to years of transplant. (C) OS according to donor type in patients transplanted between 2008 and 2018 (n = 19).

The 3-year EFS for the cohort was 78% (95% CI, 56-91). Of the 3 patients (patients 2, 5, and 22) who had graft failure, 2 died (patients 2 and 22) during second transplant (1 cerebral hemorrhage, 1 pneumonitis). Patient 5 underwent a successful second transplant with good immune reconstitution but died of urosepsis 3.8 years later.

Donor chimerism, immune reconstitution, and long-term disease outcome

Long-term follow-up data, available for 14 transplant survivors, are shown in Table 4. The median age of long-term survivors was 5.3 years (range, 2.2-14), with a median duration of follow-up of 3.5 years (range, 1.1-7.3). The median donor myeloid and lymphocyte chimerism at last follow-up (n = 19) was 100% (range, 0-100) and 100% (range, 64-100), respectively. Immune-reconstitution kinetics within the first 12 months was available for 18 of 19 survivors (1 patient was excluded for on-going active GvHD treatment; Figure 2). Compared with disease controls, patients transplanted for MHC class II deficiency had significantly lower CD4+ T-lymphocyte counts at 5 months (P =.06), 6 months (P = .01), and 12 months (P = .002) posttransplant, as well as at latest follow-up (P = .01) (Figure 3). Although 7 survivors (50%) had low or low-normal CD4+ T lymphocytes at last review, the remainder had CD4+ T-lymphocyte counts in the normal range. There was no significant difference in circulating CD3+ cells (P = .61), CD8+ cells (P = .59), CD19+ cells (P = .90), NK cells (P = .22), or percentage of activated T lymphocytes (HLA-DR) (P = .66) between patients and controls at any time point posttransplant. Donor type had no impact on immune reconstitution kinetics (supplemental Figure 1, available on the Blood Web site). All long-term survivors were well, with no end organ damage (Table 4). Patient 14 had good neurological recovery after enterovirus meningitis with communicating hydrocephalus. All survivors were off Ig replacement and had protective vaccine responses. None had any significant infection or autoimmunity.

Table 4.

Immunological features and donor chimerism of long-term transplant survivors at last follow-up (>1 y post-HCT)

No/year of HCTAge at follow-up, yTime post-HCT, yClinical statusDonor chimerismLymphocyte subset (cells/µL) at last follow-upDR expression (%)Stop IVIg replacement (time post-HCT), moIg (g/L)Vaccine response
CD3CD19CD4CD8CD4/CD8 ratioTotal naive T cellsT*BMGAMTetHib
4/2003 5.5 4.0 Well CD15, 85%; CD3, 98%; CD15, 60%. Pre-HCT 1409 1167 249 1109 0.22 ND Yes (9) 13.0 1.05 1.06 0.81 >9.0 
Post-HCT 1884 332 310 1156 0.26 NA 23 ND ND 
7/2011 8.1 7.3 Well CD15, 42%; CD3, 81%; CD19, 76%. Pre-HCT 331 (↓) 443 106 222 0.48 162 Yes (9) 11.9 1.66 0.58 >7.0 5.4 
Post-HCT 1660 545 399 1079 0.37 697 10 BD ND 
8*/2012 14 7.2 Well. Unassisted menarche. CD15, 94%; CD3, 69%; CD19, 95%. Pre-HCT 3851 956 519 3203 0.16 616 Yes (9) 11.1 1.73 1.09 0.32 6.4 
Post-HCT 1106 327 201 829 0.24 353 16 92 95 
9*/2012 9.5 7.1 Well CD15, 8%; CD3, 8%; CD19, 59%. Pre-HCT 4478 3009 989 3520 0.28 1165 Yes (13) 12.0 <0.04 1.15 4.00 >9.0 
Post-HCT 2375 770 503 1669 0.30 1093 11 
10/2015 4.4 3.0 Well CD15, 0%; CD3, 64%. Pre-HCT 1402 1056 777 553 1.40 686 Yes (12) 7.4 0.81 0.61 1.68 ND 
Post-HCT 1127 340 326 680 0.48 315 ND 29 
11/2015 6.2 3.8 Well WB, 100%. Pre-HCT 1059 1163 453 209 2.17 ND Yes (10) 8.4 1.1 1.1 ND ND 
Post-HCT 3700 650 1900 1260 1.51 ND ND 100 ND 
12*/2015 4.8 3.7 Well WB 100% at 6 mo post-BMT Pre-HCT 6011 1987 1581 300 5.27 300 Yes (13) NA NA NA ND ND 
Post-HCT 2232 298 804 952 0.84 NA ND ND ND 
13*/2015 4.8 3.6 Well WB 100% at 6 mo post-HCT Pre-HCT 1015 1621 695 209 3.32 233 Yes (12) NA NA NA 0.76 ND 
Post-HCT 2413 340 959 1114 0.85 ND ND ND ND 
14/2015 5.1 3.4 Good neurological recovery but speech delay WB 100% at 9 mo post-HCT Pre-HCT 1474 1529 1097 277 3.96 575 Yes (15) 14.2 <0.05 1.28 0.56 ND 
Post-HCT 1956 460 863 604 1.43 ND 19 ND ND 
16/2016 2.8 2.0 Well WB 100% at 4 mo post-HCT Pre-HCT 4327 939 3126 1106 2.83 2682 16 ND 62 Yes (12) 5.74 0.41 0.32 3.77 ND 
Post-HCT 2398 371 1238 1373 0.90 1077 
17/2017 4.2 1.6 Well CD15, 100%; CD3, 100%. Pre-HCT 744 198 172 265 0.68 NA Yes (14) 7.7 0.66 0.97 2.23 ND 
Post HCT 2251 894 704 844 0.83 ND ND ND ND 
19*/2017 8.1 1.3 Well WB 100% at 5 mo post-HCT Pre-HCT 1555 324 378 648 0.58 218 Yes (16) NA NA NA 3.04 ND 
Post-HCT 1357 847 516 649 0.80 NA ND ND ND 
20/2017 2.2 1.2 Well WB 100% at 6 mo post-HCT Pre-HCT 1551 (↓) 797 849 530 1.60 ND Yes (12) 5.5 0.25 0.49 ND ND 
Post-HCT 2227 292 1092 710 1.53 ND 30 ND 70 
21*/2017 6.3 1.1 Well WB 100% at 5 mo post-HCT Pre-HCT 207 (↓) 58 (↓) 71 117 0.60 49 Yes (11) NA NA NA 0.09 ND 
Post-HCT 2337 947 516 649 0.80 NA ND ND ND 
No/year of HCTAge at follow-up, yTime post-HCT, yClinical statusDonor chimerismLymphocyte subset (cells/µL) at last follow-upDR expression (%)Stop IVIg replacement (time post-HCT), moIg (g/L)Vaccine response
CD3CD19CD4CD8CD4/CD8 ratioTotal naive T cellsT*BMGAMTetHib
4/2003 5.5 4.0 Well CD15, 85%; CD3, 98%; CD15, 60%. Pre-HCT 1409 1167 249 1109 0.22 ND Yes (9) 13.0 1.05 1.06 0.81 >9.0 
Post-HCT 1884 332 310 1156 0.26 NA 23 ND ND 
7/2011 8.1 7.3 Well CD15, 42%; CD3, 81%; CD19, 76%. Pre-HCT 331 (↓) 443 106 222 0.48 162 Yes (9) 11.9 1.66 0.58 >7.0 5.4 
Post-HCT 1660 545 399 1079 0.37 697 10 BD ND 
8*/2012 14 7.2 Well. Unassisted menarche. CD15, 94%; CD3, 69%; CD19, 95%. Pre-HCT 3851 956 519 3203 0.16 616 Yes (9) 11.1 1.73 1.09 0.32 6.4 
Post-HCT 1106 327 201 829 0.24 353 16 92 95 
9*/2012 9.5 7.1 Well CD15, 8%; CD3, 8%; CD19, 59%. Pre-HCT 4478 3009 989 3520 0.28 1165 Yes (13) 12.0 <0.04 1.15 4.00 >9.0 
Post-HCT 2375 770 503 1669 0.30 1093 11 
10/2015 4.4 3.0 Well CD15, 0%; CD3, 64%. Pre-HCT 1402 1056 777 553 1.40 686 Yes (12) 7.4 0.81 0.61 1.68 ND 
Post-HCT 1127 340 326 680 0.48 315 ND 29 
11/2015 6.2 3.8 Well WB, 100%. Pre-HCT 1059 1163 453 209 2.17 ND Yes (10) 8.4 1.1 1.1 ND ND 
Post-HCT 3700 650 1900 1260 1.51 ND ND 100 ND 
12*/2015 4.8 3.7 Well WB 100% at 6 mo post-BMT Pre-HCT 6011 1987 1581 300 5.27 300 Yes (13) NA NA NA ND ND 
Post-HCT 2232 298 804 952 0.84 NA ND ND ND 
13*/2015 4.8 3.6 Well WB 100% at 6 mo post-HCT Pre-HCT 1015 1621 695 209 3.32 233 Yes (12) NA NA NA 0.76 ND 
Post-HCT 2413 340 959 1114 0.85 ND ND ND ND 
14/2015 5.1 3.4 Good neurological recovery but speech delay WB 100% at 9 mo post-HCT Pre-HCT 1474 1529 1097 277 3.96 575 Yes (15) 14.2 <0.05 1.28 0.56 ND 
Post-HCT 1956 460 863 604 1.43 ND 19 ND ND 
16/2016 2.8 2.0 Well WB 100% at 4 mo post-HCT Pre-HCT 4327 939 3126 1106 2.83 2682 16 ND 62 Yes (12) 5.74 0.41 0.32 3.77 ND 
Post-HCT 2398 371 1238 1373 0.90 1077 
17/2017 4.2 1.6 Well CD15, 100%; CD3, 100%. Pre-HCT 744 198 172 265 0.68 NA Yes (14) 7.7 0.66 0.97 2.23 ND 
Post HCT 2251 894 704 844 0.83 ND ND ND ND 
19*/2017 8.1 1.3 Well WB 100% at 5 mo post-HCT Pre-HCT 1555 324 378 648 0.58 218 Yes (16) NA NA NA 3.04 ND 
Post-HCT 1357 847 516 649 0.80 NA ND ND ND 
20/2017 2.2 1.2 Well WB 100% at 6 mo post-HCT Pre-HCT 1551 (↓) 797 849 530 1.60 ND Yes (12) 5.5 0.25 0.49 ND ND 
Post-HCT 2227 292 1092 710 1.53 ND 30 ND 70 
21*/2017 6.3 1.1 Well WB 100% at 5 mo post-HCT Pre-HCT 207 (↓) 58 (↓) 71 117 0.60 49 Yes (11) NA NA NA 0.09 ND 
Post-HCT 2337 947 516 649 0.80 NA ND ND ND 

Normal tetanus antibody reference range: 0.01 to 10 IU/mL. Normal Haemophilus influenzae antibodies: 1.0-20 mg/L.

B, B cells; BMT, bone marrow transplantation; Hib, Haemophilus influenzae type b antibodies; M, monocytes; NA, not available; ND, not done; T, T cells; Tet, tetanus; WB, whole blood. ↓, below normal reference range for age.

*

T cells were not activated in DR expression. (Siblings: 8 and 9; 12 and 13; 19 and 21.)

Below normal reference range for age.

Figure 2.

Immune reconstitution kinetics posttransplant. Mean CD3+ cells (A), mean CD4+ cells (B), mean CD19 cells (C), mean CD8 cells (D), mean activated T cells (E), and mean NK cells (F) were measured at different time points posttransplant. Disease controls (n = 36) included patients who were transplanted for SCID (n = 10), CD40 ligand deficiency (n = 2), Wiskott-Aldrich syndrome (n = 7), chronic granulomatous disease (n = 13), and other PID (n = 4; 1 NK deficiency, 1 inducible costimulator deficiency, 1 hemophagocytic lymphohistiocytosis, 1 combined immunodeficiency). *P = .06, **P < .05.

Figure 2.

Immune reconstitution kinetics posttransplant. Mean CD3+ cells (A), mean CD4+ cells (B), mean CD19 cells (C), mean CD8 cells (D), mean activated T cells (E), and mean NK cells (F) were measured at different time points posttransplant. Disease controls (n = 36) included patients who were transplanted for SCID (n = 10), CD40 ligand deficiency (n = 2), Wiskott-Aldrich syndrome (n = 7), chronic granulomatous disease (n = 13), and other PID (n = 4; 1 NK deficiency, 1 inducible costimulator deficiency, 1 hemophagocytic lymphohistiocytosis, 1 combined immunodeficiency). *P = .06, **P < .05.

Figure 3.

Lymphocyte subsets at latest follow-up (>1 year posttransplant). CD3+ cells (A), CD8+ cells (C), and CD19+ (D) cells were comparable between patients with MHC class II deficiency (n = 14) and controls. (B) CD4+ cells were significantly lower in patients with MHC class II deficiency compared with controls (P = .01). (E) There was no significant difference in CD4+ cells before and after transplant in patients with MHC class II deficiency. (F) Pre- and posttransplant CD4+ cells in individual patients and controls.

Figure 3.

Lymphocyte subsets at latest follow-up (>1 year posttransplant). CD3+ cells (A), CD8+ cells (C), and CD19+ (D) cells were comparable between patients with MHC class II deficiency (n = 14) and controls. (B) CD4+ cells were significantly lower in patients with MHC class II deficiency compared with controls (P = .01). (E) There was no significant difference in CD4+ cells before and after transplant in patients with MHC class II deficiency. (F) Pre- and posttransplant CD4+ cells in individual patients and controls.

Discussion

This is one of the largest HCT series for MHC class II deficiency from a single transplant center over the past 2 decades. A number of important observations emerge from this report. Although the majority of patients present with classical clinical and immunological features, some patients can have noninfectious manifestations and an unusual pattern of laboratory results. OS has improved significantly, and no patient had severe acute GvHD or chronic GvHD. Despite numerically decreased CD4+ T-lymphocyte reconstitution, all transplant survivors had a good immunological outcome.

Children with MHC class II deficiency usually present with a clinical phenotype that is very similar to SCID and generally have severe CD4+ T lymphocytopenia, hypogammaglobulinemia, and lack of antigen-specific antibody responses. The CD4+ lymphocytopenia reflects the abnormal CD4+ thymocyte development due to defective MHC class II expression in the thymus. CD8+ T-lymphocyte counts may be normal or raised, leading to an inverted CD4/CD8 ratio. The diagnosis is confirmed by absent or very low HLA-DR expression on lymphocytes, which is the immunological hallmark of the disease. In our cohort, 6 patients (24%) had a normal CD4+ T-lymphocyte count, 4 patients (16%) had a high CD8+ T-lymphocyte count, and 8 patients (32%) had a normal CD4/CD8 ratio. Autoimmunity was the first presentation in patient 8, who was treated with multiple biologic agents for refractory arthritis before the diagnosis of MHC class II deficiency was made. She and her younger sibling (patient 9), both of whom had homozygous CIITA mutation, developed macrophage activation syndrome prior to transplant, which has not been reported previously. Although disseminated BCGosis (disseminated infection) is not expected in these patients because of the presence of residual immunity in the form of CD8+ T lymphocytes and NK cells, 1 patient in our cohort had disseminated BCGosis prior to transplant.

We have shown that the 3-year OS has improved to 94% for children with MHC class II deficiency transplanted since 2008, which is comparable to HCT for children with severe combined immunodeficiency.3,6-10  Small et al reported transplant survival of 69% in 16 children with MHC class II deficiency from 5 transplant centers in Europe and the United States.11  Al-Mousa et al12  reported a similar transplant survival of 66% in a cohort of 30 patients from a single transplant center in Saudi Arabia. Many factors have contributed to this improvement in Great North Children's Hospital, including a detailed graft selection hierarchy, superior HLA-matching technology, improved methods for graft manipulation, improved supportive care, vigilant infection surveillance and preemptive treatment, more effective antimicrobial therapy, and a multidisciplinary team approach prior to and after HCT. In our center, we have used RTC with fludarabine, treosulfan, and alemtuzumab for family and UD transplants since 2009. Our haploidentical transplant strategy in this cohort includes conditioning with fludarabine, treosulfan, thiotepa, ATG (Grafalon), and rituximab and graft manipulation by TCRαβ/CD19 depletion of PBSCs. The OS following haploidentical transplant in our cohort was comparable with family and UD transplants, with a single fatality. Despite being diagnosed at 6 months of age, the deceased patient was referred for transplant at 6 years, by which time he had multiple viral infections, gut failure, and chronic lung disease. The use of alemtuzumab and graft engineering has reduced the incidence of acute GvHD in our cohort compared with the high reported incidence ranging from 47% to 73%.9,12,13  A high incidence of acute GvHD in previous studies may be due to inadequate in vivo T-lymphocyte depletion and chronic viral infection. Despite the fact that pre-HCT enteropathy is common in our study cohort, no patient had gut GvHD.

The long-term disease outcome in our cohort is excellent, with good immunological outcomes, no infections, and recovery of previous organ damage. In contrast to Klein et al’s observation of persistent CD4+ lymphopenia in all 8 transplant survivors in their series of 19 transplants, 50% (n = 7) of the survivors have normal CD4+ lymphocytes posttransplant.7  Godthelp et al described an impaired immune repertoire in 2 patients with partial engraftment post-HCT.14  The persistent CD4+ T lymphopenia in some patients might be explained by impaired thymocyte maturation caused by defective MHC class II expression on thymic epithelia. Our cohort with the largest series of transplant survivors showed that, despite low CD4+ T-lymphocyte numbers, transplanted patients exhibit normalization of antigen-specific T-lymphocyte stimulation and antibody production in response to immunization antigens. However, the long-term impact of decreased CD4+ T-lymphocyte reconstitution is unclear, particularly the risks of autoimmunity and premature immunosenescence.

In conclusion, HCT is a safe curative therapy for children with MHC class II deficiency. Unrelated and parental HIDs are associated with excellent survival at Great North Children's Hospital, comparable to MFDs. Because young age at HCT is associated with a favorable outcome in children with MHC class II deficiency, HCT should be performed as early as possible after the diagnosis, before the onset of disease-related organ damage.7  Family screening plays an important role in advancing the transplant care for children with MHC class II deficiency. There is a need for a multicenter study using registry data to delineate the predictors of transplant survival and long-term disease outcomes in children with MHC class II deficiency. Advances in graft manipulation, as well as additional cellular therapy and patient-tailored conditioning regimens, may enable precise personalized transplant care and further improve transplant survival while reducing late effects, such as infertility. In addition, it is conceivable that, in the future, gene therapy may offer an alternative option for children with MHC class II deficiency.

For original data, please contact Su Han Lam (s.lum@nhs.net).

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Acknowledgments

The authors thank all patients and their families, as well as the treating multidisciplinary team.

Authorship

Contribution: S.H.L. collected data, performed the statistical analysis, interpreted data, and prepared the manuscript; M.S. and A.R.G. conceptualized the research, performed statistical analysis, interpreted data, and wrote and critically reviewed the manuscript; C.A., P.M., B.M., H.W., B.A.-S., D.A.-Z., H.A.-M., W.A.-H., H.A.A., B.S., S. Habibollah, R.M., and L.G. collected the data and reviewed the manuscript; A.F., E.W., K.E., and M.E. reviewed the manuscript; and T.F., S.O., Z.N., S. Hambleton, A.C., and M.A. critically reviewed the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Su Han Lum, Clinical Resource Building, Floor 4, Block 2, Great North Children’s Hospital, Queen Victoria Rd, Newcastle upon Tyne NE1 4LP, United Kingdom; e-mail: s.lum@nhs.net.

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Author notes

*

A.R.G. and M.S. contributed equally to this work.

Supplemental data