Background and Aims

Haematopoietic cell transplantation (HCT) is the only curative therapy for MHC class II expression deficiency.

Methods

We examined the outcome of 25 children with MHC class II deficiency who received a HCT at the Great North Children’s Hospital between 1995 and 2018. Outcomes included overall survival (OS), toxicity and long-term outcome. Log rank test was used to analyse predictors of OS.

Results

Median age of transplant was 21.4 months (range, 0.9-93.3). The 3-year OS for the entire cohort was 78%, increasing to 94% for HCT after 2008 (n=19) vs 33% for HCT before 2008 (n=6) (Figure1). After 2008, the OS was comparable between matched family (100%), unrelated (100%) and parental haploidentical donor recipients (85%) (Figure2). Three had graft failure and received a second transplant but died. 9 patients had grade 1 acute GvHD (36%), 4 (14%) grade II, none grade III-IV and none had chronic GvHD.

Of 14 long-term survivors with evaluable data, the median age at last follow-up was 5.2 years (range, 2.2 to 14) with the median duration of follow-up 3.5 years (range, 1.1 to 7.2). All were off immunoglobulin. Median myeloid chimerism was 100% (range, 0-100) and median T-lymphocyte chimerism was 100 (range, 59-100). The median CD count was 754 x109/L (range, 201 to 1900). 4 had CD4 lymphopenia.

Conclusions

Transplant survival has improved and long-term disease outcome of survivors is good.

Background and Aims

Recurrent infections and non-infectious inflammation still limit quality of life and life expectancy in Chronic Granulomatous Disease (CGD). Continuous anti-infectious prophylaxis and immunosuppression (Conventional treatment (CT)) improve the prognosis but only stem cell transplantation (SCT) can cure the disease. However, it remains debated whether all patients with CGD benefit from SCT, whether active infections and non-infectious inflammation are still risk factors and at what age SCT should be performed.

Methods

We describe 104 patients with CGD, recruited from 6 participating centers and in collaboration with the ESID registry. 50 of whom underwent SCT and 54 remained on CT. We compared incidence and frequency of infections, non-infectious inflammation, hospitalizations, operations, and immune modulating therapy.

Results

With CT 84,6% of patients suffered from at least one infection, 75% from non-infectious inflammation. Patients on CT developed infection/inflammation or needed hospitalization/surgery at a median of 1,87 per year (IQR [0,94-4,24]), versus 7 (IQR [5-10,9]) in the first year after SCT but none of the patients undergoing SCT developed severe complications after the initial year following SCT (IQR [0-0,53]). Complications decreased (p <.05) and growth improved significantly after SCT (weight (p.017), height (p.029)). Nevertheless, complications post-SCT remain frequent: 8% had extended chronic GvHD, 16% initial graft failure, 12% died. Age > 8 years at SCT and active complications at SCT coincided with an increased risk for complications.

Conclusions

Infections, non-infectious inflammation and failure to thrive occur in all patients with CGD on CT. SCT can cure the disease, but age and disease activity must be considered in an individualized risk/benefit assessment.

Background and Aims

Progressive multifocal leukoencephalopathy (PML), an opportunistic JCV infection with poor prognosis, has no effective treatment. Programmed cell death-1 (PD-1) and its ligand (PD-L1) function as T-cell co-inhibitors, pivotal in the T-cell–exhaustion pathway frequently involved in chronic viral infections.

Methods

Hypothesizing that PD-1 blockade might abrogate T-cell exhaustion, and control JCV replication and PML course, we gave a 53-year-old PML patient nivolumab salvage therapy.

Results

All clinical and imaging signs regressed, with only residual sequelae, and JCV was completely cleared from cerebrospinal fluid. No immune reconstitution inflammatory syndrome or related adverse events occurred.

Analyses of the T-cell infiltrate and PD-1/PD-L1 expression in a pretreatment brain biopsy showed: intense PD-L1 expression on CD163+ parenchymal macrophages; high PD-1 expression on CD4+ and CD8+ T cells; and PD-L1+ macrophage and T-cell co-localization, supporting their partnership in immune exhaustion and virus escape. tory syndrome or related adverse events occurred.

Conclusions

To conclude, targeting an immune checkpoint, e.g. PD-1, to boost host defenses against JCV appears to be a promising and safe therapeutic option for PML but requires prospective studies.

Background and Aims

We report on a male patient with a history of recurrent generalized Epstein Barr virus (EBV) positive lymphoproliferation starting with the diagnosis of EBV-positive Hodgkin lymphoma at the age of 4 years. He was born as 2^nd child to consanguineous arabic parents. His older brother is healthy. On arrival at our institution with nine years of age he presented with a generalized EBV-positive diffuse large B-cell lymphoma (DLBCL). In a previously initiated “whole exome sequencing” approach a homozygous mutation in TNFRS9 encoding 4-1BB or CD137 had been detected (Alosaimi et al., JACI 2019). 4-1BB is a costimulatory molecule expressed on activated T cells and upon ligation induces a signaling cascade that results in T cell proliferation, cytokine secretion and enhanced effector function.

Methods

According to the immunohistology of the DLBCL we initiated a therapy consisting of daratumumab (anti-CD38 mAb), bortezomib (proteasome inhibitor), dexamethasone and rituximab (anti-CD20 mAb) to achieve clinical and radiological regression of his lymphoma, followed by an allogenic hematopoietic stem cell transplantation (HSCT) from a 10/10 matched unrelated donor, after conditioning with Busulfan (targeted AUC 80mg/l*h), Fludarabine, Thiotepa and Alemtuzumab.

Results

He is currently well and in an excellent clinical condition 4 months after HSCT with complete donor chimerism and clinical remission of the lymphoma.

Conclusions

Patients with a history of recurrent EBV-positive lymphoma on the basis of a primary immunodeficiency caused by mutations in TNFRS9 should be considered for HSCT for permanent cure of the disease.

Background and Aims

Treatment for X-Linked agammaglobulinaemia (XLA) is IgG replacement, which lacks IgA and IgM. Patients remain at continued risk of respiratory tract infections and potentially bronchiectasis. This observational study analysed the quality of life (QoL) in UK XLA patients to ascertain if novel therapies are justified, most notably newborn screening and gene therapy.

Methods

QoL data were collected from 53 patients with a definitive diagnosis of XLA using validated, self-reporting questionnaires and compared against healthy norms and patients with cystic fibrosis (CF).

Results

Paediatric QoL scores were not significantly different from healthy norms or CF patients. Adult QoL scores were not significantly different from UK norms, apart from general health, which was significantly lower in XLA patients (Figure 1). Patients with bronchiectasis had significantly worse QoL than patients without bronchiectasis for all sections apart from pain. Adult QoL scores correlate strongly with their FEV1 Z-Scores (rho = 0.697, p = 0.006). XLA patients have significantly worse respiratory health-related QoL compared to UK healthy norms and are comparable to CF (Figure 2).

(* p<0.05, ** p<0.005)

Conclusions

In the absence of bronchiectasis, XLA patients tend to have a normal QoL. However, bronchiectasis is associated with significantly worse QoL, which is similar to patients with cystic fibrosis and correlates strongly with patient’s lung function results. The prevention of bronchiectasis should therefore be a priority for XLA patients, which may be difficult given the limitations in current therapies.

Background and Aims

We have recently demonstrated that early-onset Waldmann’s protein-losing enteropathy can be caused by CD55 mutations and established the pathogenic role of complement activation in intestinal lymphangiectasia and severe thromboses (CHAPLE syndrome). We sought to evaluate the therapeutic efficacy of eculizumab, a monoclonal antibody against C5 in CHAPLE patients and investigate the molecular signatures and potential biomarkers.

Methods

Fifteen patients with CHAPLE syndrome received eculizumab for a mean of 12.3 months and were carefully monitored for effects on disease and adverse events. Outcome parameters included clinical symptoms, blood chemistry, nutrition, quality of life scores, structural gastrointestinal abnormalities, and malabsorption indices. SOMALogic assay investigated pathological serum signatures of CHAPLE syndrome and their dynamic changes in response to therapy.

Results

Eculizumab provided an immediate effect in all patients, with a gradual increase in total protein, albumin and immunoglobulin levels, which are completely restored within 4 weeks. Symptom diaries demonstrated a significant decrease in the scores of nausea, vomiting, abdominal pain and facial edema, and reduced number of bowel movements. Eculizumab reversed hematological abnormalities and intestinal malabsorption and led to a significant improvement in growth indices and overall health outcomes over time. Importantly, life threatening complications of CHAPLE syndrome were ameliorated, and patients were able to discontinue prior medications including those which were associated with significant adverse effects. Unintentional discontinuation of eculizumab longer than 6 weeks led to a relapse of symptoms. We detected major alterations in numerous biomolecules in the serum samples.

Conclusions

Eculizumab proved safe and highly effective in CHAPLE syndrome.

Background and Aims

Primary immunodeficiency disorders (PIDs) result in recurrent infections and a predisposition to malignancy due to impaired immune surveillance.¹Large registry studies have demonstrated a 1.42-fold excess relative risk of malignancy, with lymphoproliferative disorders the most common.²Allogeneic haematopoietic stem cell transplantation (alloHSCT) is the only curative option for most PIDs.³Recently, reduced intensity conditioned alloHSCT has been shown to be effective and safe in adults with PID.^4,5PID associated malignancy is often a trigger for alloHSCT in adult PID patients.

Methods

Evidence from the paediatric population suggests the presence of malignancy in PID patients should not preclude alloHSCT.⁶ There is scant data on alloHSCT outcome in adult PID patients with a history of malignancy. We compared overall survival (OS) between patients with a history of a malignancy (n= 12) and those without (n=35) in our cohort of (n=47) teenagers and young adults (aged >13, median 22) with PID (Fig 1). The patients in the malignant group had haematological (6 MDS, 3 Hodgkin Lymphoma, 1 B-cell NHL, 1 T-cell NHL, 1 autoimmune lymphoproliferative disorder) and epithelial malignancies (2 VIN/CIN/AIN and 1 poorly differentiated squamous cell carcinoma). Patients with lymphoma were in remission prior to transplant.

Results

OS in the patients with malignancy was 100% (median follow up 4 years) with no recurrence of malignancy post-transplant(vs 82.9% in the non-malignant group, p=0.147).

Conclusions

AlloHSCT may be particularly useful in adult patients with PID-associated malignancy as the restoration of immune surveillance and provision of a life-long graft-vs-tumour effect may reverse the inherited predisposition to malignancy.

Background and Aims

Parental donors provide rapid access to children with PID who lack of matched donors, which enables early transplant and improves survival.

Methods

We report the outcomes of 97 children with PID who received first parental haploidentical transplantation (HIT) between 1987 and 2018 at the Great North Children’s Hospital, Newcastle upon Tyne.

Results

Transplantation characteristics and outcomes summarised in table. There was increased use of HIT in children with non-SCID over the past 10 years (MHC class II deficiency, 6; CGD, 4; WAS, 3; DOCK8 deficiency, 3; others, 19) . Engraftment kinetics (p=0.001) improved and graft failure (p=0.01) reduced with CD3/CD19-TCD-PBSC and TCR-µb/CD19-depleted-PBSC. The incidence of acute GvHD was similar and none had chronic GvHD. Analysis by TCD methods revealed that the OS and EFS were superior for TCR-ab/CD19-depleted-PBSC compared to CD3/CD19-depleted-PBSC, CD34-selected marrow and Campath-M depleted marrow. The myeloid donor chimerism was better using the newer methods.

Conclusions

Parental HIT using TCR-ab/CD19-depleted-PBSC is a safe alternative donor procedure and leading to successful outcome even in non-SCID PID.