Michael H. Albert’s research while affiliated with Ludwig-Maximilians-Universität in Munich and other places

Background ARPC1B deficiency leads to a combined immunodeficiency characterized by early clinical onset, recurrent infections, and platelet abnormalities with bleeding tendency. Although most patients with ARPC1B mutations tolerate transplant conditioning, with a high rate of immunodeficiency resolution, there is a lack of studies comparing the clinical outcome and quality of life of patients undergoing transplantation or treated conservatively. The aim of the study is to compare ARPC1B patients managed conservatively and with HSCT assessing clinical outcome and quality of life. Methods The study was approved by ESID, EBMT, and CIS inborn error working parties. The inclusion criteria are patients with ARPC1B deficiency genetically confirmed and treated conservatively or with HSCT. Clinical data including symptoms, genetics, IDDA 2.1 score at last follow-up, and HSCT-related features were collected by local physicians and anonymized. Patients included in the study completed age-related quality of life questionnaires: PedsQL 4.0 and SDQ for children and SF 12 for adults, respectively. Results Thirteen centers from nine countries have been involved, collecting data from 20 patients. Clinical onset was early in all patients (median age 1 month [0-36]). The most frequent homozygous variant was c.311G>C (20%). Eight out of the 20 patients (40%) received allo-HSCT at a median age of 8.8 years [0.76-16.2]. The main clinical features are summarized in Table 1. At last available follow-up, 17 out of 20 patients are alive (85%), with 3 out of 8 patients dead after transplant. The median age at follow-up was 10.41 (1.58-36) for non-transplanted and 14.85 years (0.83-22.2) for transplanted patients. At the time of writing, 10 out of 17 patients (58.8%) had completed the QoL questionnaire (8/12 not transplanted, 2/5 transplanted). Preliminary results from the quality of life questionnaires are highlighted in Figure 1A-B. Table 1. HSCT No-HSCT Total n n=8 100% n=12 % n=20 (100) Infections 8 100 11 92 19 (95%) Recurrent AOM 4 50 9 75 13 (65%) URTI 5 62.5 3 25 8 (40%) LRTI 5 62.5 6 50 11 (55%) Sepsis 3 37.5 0 0 6 (30%) CNS infections 0 0 1 8 3 (15%) Skin infections 6 75 9 75 15 (75%) Severe Warts 2 25 4 33 6 (30%) Acute/Chronic CMV 2 25 4 33 7 (35%) Bleeding 3 37.5 8 67 11 (55%) Enterorrhagia 3 37.5 7 58 10 (50%) Recurrent epistaxis 0 0 2 17 2 (10%) ITP 3 37.5 3 25 6 (30%) Severe eczema 6 75 8 67 14 (70%) Skin vasculitis 2 25 5 42 7 (35%) Arthritis 2 25 4 33 6 (30%) Lymphoproliferation 2 25 1 8 3 (15%) IBD-like 2 25 4 33 6 (30%) Last follow-up IDDA 2.1 score 32.9 [4.1-174] 33.9 [6.9-66] 32.9 [4.1-174] HSCT: Hematopoietic Stem Cell Transplantation; AOM: Acute Otitis Media; URTI: Upper Respiratory Tract Infection; LRTI: Lower Respiratory Tract Infection; CNS: Central Nervous System; CMV: Cytomegalovirus; ITP: Immune Thrombocytopenic Purpura; IBD: Inflammatory Bowel Disease; IDDA: Inflammatory Disease Damage Assessment Figure 1. Patient (A) and proxy (B) PedsQL 4.0 scales scores of pediatric patients with ARPC1B deficiency. Scores are compared with children with healthy pediatric population. Conclusion Preliminary results confirm that HSCT in ARPC1B deficiency is feasible and effective. Even if preliminary, QoL was significantly reduced in patients treated conservatively compared with healthy donors. Notably, there is a marked reduction in the frequency of bleeding, eczema, and autoimmune/autoinflammatory symptoms in the HSCT group. More data are needed to determine its impact on patient outcomes and quality of life.

Wiskott-Aldrich Syndrome (WAS) is a rare X-linked disorder, characterized by thrombocytopenia, eczema, recurrent infections, autoimmunity and malignancy. Here we discuss current conservative and definitive approaches to treating WAS, based on recently published evidence. Disease severity in WAS is highly variable. Recent studies confirm that the probability of disease progression depends on the type of genetic variant, supporting early diagnosis and tailored treatment strategies. Milder cases, historically termed X-linked thrombocytopenia (XLT), received supportive care, while severe cases were referred for standard allogeneic hematopoietic cell transplantation (HCT) or gene therapy (GT) in clinical trials. Advances in HCT and GT, together with recent knowledge that even "XLT" patients are at risk for severe immune complications, suggest that most young patients with WAS should be offered a potentially curative approach at diagnosis. Older patients with a small subset of milder variants may be treated conservatively unless they develop life-threatening autoimmune or malignant complications; regular monitoring and proactive management are critical to preventing irreversible complications. We recommend discontinuing the term XLT as it implies a mild and uncomplicated disease, which is not the norm, and instead tailor treatment for all WAS patients to their individual genetic profile, disease severity, and clinical course.

Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by defective NADPH oxidase function, leading to impaired microbial killing, recurrent infections and granulomatous inflammation. Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, particularly effective when a fully HLA-matched donor is available. However, the place of HLA-haploidentical HSCT remains less established. This retrospective, multicenter study analyzed outcomes of 64 CGD patients (53 males, 46 with X-linked CGD) who underwent a first HSCT with HLA-haploidentical family donors either with in vitro TCRαβ/CD19 depletion or in vivo depletion using post-transplant cyclophosphamide (PTCY). The mean age at transplant was 5.8 years (0-33 years). Patients exhibited a high disease burden prior to HSCT, with 45% experiencing infections in the 6 months prior to HSCT and 67% exhibiting inflammation. Outcomes in the entire cohort showed a 3-year overall survival (OS), event-free survival (EFS) and GvHD grade III to IV-free, event-free survival (GEFS) of 75.9%, of 70.2%, and of 56.1% respectively and were not impacted by the type of depletion or age. The cumulative incidence (CI) of primary graft failure was 20.6%. The CI of grade II to IV acute GvHD was higher in the PTCY group (p=0.04) whereas the CI of GVH grade III to IV was not. These results indicate that HLA-haploidentical HSCT is a feasible transplant option for CGD patients lacking HLA-matched donors. Further refinement of transplant protocols is necessary to mitigate graft failure and acute GvHD, ultimately improving access and outcomes for this life-saving therapy.

The European Society for Immunodeficiencies patient registry (ESID-R), established in 1994, is one of the world's largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R structure, data content, and impact. The registry includes 30,628 patient datasets (aged 0-97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings highlight real-world observations of IEI diagnoses, genetic causes, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. Early declining survival probabilities for many IEI subcategories suggest expanding newborn screening beyond severe combined immune deficiencies. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.

Jagunal-homolog1 (JAGN1) is an endoplasmic reticulum–resident protein, which is part of the early secretory pathway and granulocyte colony-stimulating factor (CSF; G-CSF) receptor–mediated signaling. Autosomal recessively inherited variants in JAGN1 lead to congenital neutropenia, early-onset bacterial infections, aphthosis, and skin abscesses due to aberrant differentiation and maturation of neutrophils. Bone metabolism disorders and syndromic phenotype, including facial features, short stature, and neurodevelopmental delay, have been reported. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a treatment option for patients who respond poorly to therapy with G-CSF and those who suffer from complicated infections. In a retrospective multicenter study, data from 32 patients with JAGN1 deficiency were collected to describe the disease, perform phenotype-genotype analysis, and evaluate treatment modalities. Patients presented with 9 homozygous mutations in JAGN1. All patients experienced infectious complications. Twelve patients presented with short stature and facial features. Neurodevelopmental delay was observed in 4 patients from 3 families. Variant c.3G>A p.Met1, found in 9 patients, was never connected to extramedullary symptoms, except for short stature in 1 patient. Patients with the variants c.63G>T, p.Glu21Asp and c130c>T p.His44 Tyr presented more often with syndromic facial features and bone metabolism disorders. Six patients underwent allogeneic stem cell transplantation due to therapy-refractory neutropenia and severe infections, 1 received the graft because of myelodysplastic syndrome and secondary acute myeloid leukemia. Two patients had to undergo a second transplantation because of autologous reconstitution. One patient who did not undergo transplantation died at age 5 years due to pancolitis and septicemia. All 31 other patients were alive and healthy at the last follow-up.

BACKGROUND: AML SCT-BFM 2007 was a prospective, on site monitored, and standardized hematopoietic stem cell transplantation trial for patients with pediatric acute myeloid leukemia (AML). In this trial the graft was the investigational product and therefore needed approval by the Paul-Ehrlich-Institute (PEI). Here we report the outcomes of transplants with matched unrelated donors (MUDs) in comparison to matched sibling donors (MSDs). METHODS: Bone marrow as graft source was utilized in 90, peripheral blood stem cells in 50 patients. Children and adolescents with high-risk de novo AML or relapsed AML were eligible for enrolment. Between May 2010 and February 2016, 140 children (age < 12 years, n=91) and adolescents (age > 12, years, n=49) were recruited in Germany, Austria and the Czech Republic. A matched donor was either a MSD or an at least 9/10 HLA-matched MUD. Subjects with AML in CR1 (n=45) or CR2 (n=47) were conditioned with a myeloablative regiment consisting of Busulfan (age adjusted i.v. dosing: 3.2 - 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg i.v. on days -3 and -2), and Melphalan (140 mg/m2 i.v. on day -1) (BuCyMel). Graft-versus-Host disease (GvHD) prophylaxis was cyclosporine (CSA) and short-term methotrexate. Patients with MUD received anti-T-lymphocyte globuline at a dose of 20 mg/kg/day on days -3 through -1) in addition. Patients with poor response to AML induction therapy (n=48) were stratified to receive a reduced-intensity regimen consisting of a cytoreductive block with Fludarabine (30mg/m2/d i.v.), Amsacrine (100 mg/m2/d i.v.), and Cytarabine (2g/m2/d i.v.) (FLAMSA) on days -12 through -9, immediately followed by 4 Gy TBI on day -5 and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/day i.v.) on days -4 through -3. After early taper of MMF and CSA, three prophylactic donor lymphocyte infusions were scheduled on days 120, 150, and 180. ATLG was added for MUDs (20 mg/kg x d) and MSDs (10 mg/kg x d) on days -4 through -2. RESULTS: Of the 140 patients (68 female, 72 male), 99 received a graft from a MUD (10/10 n=70, 9/10 n=29), 32 from a MSD. Data on ethnicity were not collected. Nine patients without a matched donor were eligible for Haplo-HCT and excluded from this analysis. Overall survival (OS) at 4 years was 65% (SE 5%) for patients transplanted from MUD and not different from that for MDS transplants with 62% (SE 9%). Similarly, there was not difference for MUD and MSD transplants in the 4-years cumulative incidence rates (CI) of aGvHD II-IV with 33% (SE 5%) versus 28% (SE 8%), cGVHD 12% (SE 3%) versus 7% (SE 7%), relapse 28% (SE 5%) versus 34% (SE 9%), and TRM 14% (SE 4%) versus 16% (SE 6%), respectively. Patients in CR1 or CR2 conditioned with BuCyMel had a similar OS after MUD and MDS transplants of 76% (SE 5%) versus 62% (SE 10%), and similar CI rates of aGVHD II-IV 33% (SE 16%) versus 30% (SE 6%), relapse 21% (SE 5%) versus 29% (SE 10%) and TRM 12% (SE 5%) versus 17% (SE 5%). OS after FLAMSA-RIC was 33% (SE 10%) versus 63% (SE 17%) (p=0.17), and CIs of aGvHD II-IV 31% (SE 9%) versus 25% (SE 17%), relapse 46% (SE 10%) versus 50% (SE 20%), and TRM 20% (SE 8%) versus 0% (SE 0%) (p=0.18) in MUD and MSD transplants, respectively. CONCLUSION: With improving HLA-typing technology, OS and CI of chronic and acute GvHD II-IV are identical after MUD- and MSD-transplantation for pediatric AML, if ATLG is added for MUDs at a dose of 20 mg/kg x day on days -4 through -2. This result may have major ethical implications for the current use of minor sibling donors.

Background: Leukocyte adhesion deficiency type I (LAD-I) is a rare autosomal recessive inborn error of immunity caused by loss of function mutations in ITGB2, which encodes for the β2 common integrin subunit CD18, impairing leukocyte adhesion to inflamed endothelium and migration to sites of infection or injury. Allo-HSCT represents the only therapeutic option to enable survival beyond early childhood but is limited by donor availability, risk of infections, graft-versus-host disease (GvHD) and graft failure (GF). Objective: To characterize outcomes of patients with LAD-I who underwent allo-HSCT over a very recent 10-year period in a large European cohort. Methods: The European Society for Blood and Marrow Transplantation (EBMT) registry allo1 database was queried for patients with LAD-I who received an allo-HSCT using a single stem cell source between 2012 and 2021 and were under 12 years old at the time of transplant. Patient, donor, and transplant characteristics were summarized using descriptive statistics. Ninety-five percent confidence intervals (CI) were calculated for overall survival (OS) and event-free survival (EFS). EFS was defined as survival without GF and/or grade II-IV acute GvHD (aGvHD). Percentages for categories with missing patient data were calculated based on the number of patients with available data. Results: Among 56 patients with LAD-I who met the inclusion criteria, the median age at diagnosis was 2.0 months (IQR: 0.4-2.2) and median time from diagnosis to transplant was 6.8 months (IQR: 2.9-15.5). All patients received a conditioning regimen, with 80.4% receiving myeloablative conditioning. Most patients (80.4%) received serotherapy (mainly with ATG and alemtuzumab); and 98.2% received GvHD immunosuppressive prophylaxis. Among patients with available information, recipient/donor cytomegalovirus (CMV) status mismatch (−/+ and +/-) was present in 19.2% and 5.8%, respectively. Human Leukocyte Antigens (HLA) matched sibling donor (MSD) recipients comprised 39.3% of the cohort, matched unrelated family donors, 30.4%, matched unrelated donors, 12.5%, mismatched donors, 16.1% and unrelated donors, 1.8%. Transplant-related complications, including veno-occlusive disease, transplant-associated microangiopathy and renal insufficiency among others occurred in 31% of patients. Post-transplant infection-related hospitalizations occurred in 45.5% of patients. GF occurred in 16.4% of patients, while 27.3% developed aGvHD (Grade II-IV) and 7.7% developed chronic GvHD. Overall, the mortality rate was 14.3%. OS at 1 and 3 years in the total patient population was 85% (95% CI: 75-95%). Recipient/donor CMV status was significantly associated with OS (p=0.003) with mismatched -/+ and +/- recipient 1 year and 3 year survival of 57% (range: 25-89%) and 67% (range: 13-100%) respectively; 1-3 year OS was 86% (range: 60-100%) and 100% for -/- and +/+ patients (no deaths occurred between year 1 and 3). The 1-year EFS in the total patient population was 58% (range: 45-71%). EFS at 1 year was highest in MSD recipients (86% [range: 71-100%]), whereas it was lowest among patients with HLA mismatched donors (33% [range: 3-64%]). EFS at 3 years was the same as EFS at 1 year in the total patient population and across HLA matched subgroups, as no additional events were recorded after the first year post-transplant in any group. Conclusions: Allo-HSCT is the current standard-of-care for definitive treatment for LAD-I. However, despite a better OS in patients with LAD-I undergoing allo-HSCT, GvHD, GF, and other transplant-related complications remain significant sources of transplant-related morbidity, as shown in this recent cohort. These findings highlight the need for more effective and safer treatment approaches, including possibly lentiviral-based gene therapy.

Immunodeficiency–Centromeric instability–Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003–2021, at median age 4.3 years (range 0.5–19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1–185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1–14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.