International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). OBJECTIVES: This study sought to characterize HCT outcomes in APDS. METHODS: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. RESULTS: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. CONCLUSIONS: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.

COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience.

BACKGROUND: As of November 2020, severe acute respiratory syndrome coronavirus 2 has resulted in 55 million infections worldwide and more than 1.3 million deaths from coronavirus disease 2019 (COVID-19). Outcomes following severe acute respiratory syndrome coronavirus 2 infection in individuals with primary immunodeficiency (PID) or symptomatic secondary immunodeficiency (SID) remain uncertain. OBJECTIVES: We sought to document the outcomes of individuals with PID or symptomatic SID following COVID-19 in the United Kingdom. METHODS: At the start of the COVID-19 pandemic, the United Kingdom Primary Immunodeficiency Network established a registry of cases to collate the nationwide outcomes of COVID-19 in individuals with PID or symptomatic SID and determine risk factors associated with morbidity and mortality from COVID-19 in these patient groups. RESULTS: A total of 100 patients had been enrolled by July 1, 2020, 60 with PID, 7 with other inborn errors of immunity including autoinflammatory diseases and C1 inhibitor deficiency, and 33 with symptomatic SID. In individuals with PID, 53.3% (32 of 60) were hospitalized, the infection-fatality ratio was 20.0% (12 of 60), the case-fatality ratio was 31.6% (12 of 38), and the inpatient mortality was 37.5% (12 of 32). Individuals with SID had worse outcomes than those with PID; 75.8% (25 of 33) were hospitalized, the infection-fatality ratio was 33.3% (11 of 33), the case-fatality ratio was 39.2% (11 of 28), and inpatient mortality was 44.0% (11 of 25). CONCLUSIONS: In comparison to the general population, adult patients with PID and symptomatic SID display greater morbidity and mortality from COVID-19. This increased risk must be reflected in public health guidelines to adequately protect vulnerable patients from exposure to the virus.

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

Outcome of SARS-CoV-2 Infection in 121 Patients with Inborn Errors of Immunity: A Cross-Sectional Study.

PURPOSE: There is still scarce data on SARS-CoV-2 infection in patients with Inborn Errors of Immunity (IEI) and many unresolved questions. We aimed to describe the clinical outcome of SARS-CoV-2 infection in Brazilian IEI patients and identify factors influencing the infection. METHODS: We did a cross-sectional, multicenter study that included patients of any age affected by IEI and SARS-CoV-2 infection. The variables studied were sex, age, type of IEI, comorbidities (number and type), treatment in use for IEI, clinical manifestations and severity of SARS-CoV-2 infection. RESULTS: 121 patients were included: 55.4% female, ages from six months to 74 yo (median age = 25.1 yo). Most patients had predominantly antibody deficiency (n = 53). The infection was mostly asymptomatic (n = 21) and mild (n = 66), and one child had multisystem inflammatory syndrome (MIS-C). We could not observe sex-related susceptibility, and there was a weak correlation between age and severity of infection. The number of comorbidities was higher in severe cases, particularly bronchiectasis and cardiopathy. There were no severe cases in hereditary angioedema patients. Six patients aged 2 to 74 years died, three of them with antibody deficiency. CONCLUSION: The outcome was mild in most patients, but the Case Fatality Ratio was higher than in the general population. However, the type of IEI was not a determining factor for severity, except for complement deficiencies linked to milder COVID-19. The severity of SARS-CoV-2 infection seems to be more related to older age, a higher number of comorbidities and type of comorbidities (bronchiectasis and cardiopathy).

Experience with a Reduced Toxicity Allogeneic Transplant Regimen for Non-CGD Primary Immune Deficiencies Requiring Myeloablation.

PURPOSE: A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS: We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS: Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS: Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.

COVID-19 in the Context of Inborn Errors of Immunity: a Case Series of 31 Patients from Mexico.

INTRODUCTION: Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear. OBJECTIVE: We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19. METHODS: In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure. RESULTS: We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5-20.6) µg/mL, and the median highest ferritin value was 1015 (32-10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation. DISCUSSION: Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.

Improved outcomes using unmanipulated haploidentical hematopoietic stem cells combined with third-party umbilical cord blood transplantation for non-malignant diseases in children: The experience of a single center.

BACKGROUND: Unmanipulated haploid HSCT for SAA has resulted in improved outcomes over recent years. However, studies related to unmanipulated haploid HSCs combined with tp-UCB transplantation for other types of NMD are rare. Accordingly, we present the outcomes of 109 pediatric patients with life-threatening NMD undergoing unmanipulated haploid HSCs combined with tp-UCB transplantation. PROCEDURE: We retrospectively investigated 109 pediatric patients with life-threatening NMD treated with unmanipulated haploid HSCs combined with tp-UCB transplantation in a single center. RESULTS: The median days of neutrophil and platelet engraftment were +13 and +22 days, respectively. None of the cases experienced PGF. The incidence rates for grade I-II, III-IV aGVHD and cGVHD were 44.9%, 24.8%, and 9.3%, respectively. The incidence rates of CMV and EBV viremia were 46.7% and 39.4%, respectively. The median follow-up duration was 997 days. In total, 106 patients survived, including 104 cases with FFS and 2 cases with SGF. Three patients died. The 5-year TRM, OS, and FFS were 2.8%, 97.2%, and 96.2%, respectively. CONCLUSION: The results of unmanipulated haploid HSCs combined with tp-UCB in pediatric patients with life-threatening NMD were promising. However, further research is now needed to determine specific factors that might influence the engraftment of HSCs.

Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases.

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.

Hematopoietic Stem Cell Transplantation in Children with Inborn Errors of Immunity: a Multi-center Experience in Colombia.

PURPOSE: To characterize the pediatric population with inborn errors of immunity (IEI) that was treated with hematopoietic stem cell transplantation (HSCT) in three reference centers in Colombia. What have been the characteristics and outcomes of hematopoietic stem cell transplantation in pediatric patients with inborn errors of immunity in three reference care centers in Colombia between 2007 and 2018? METHODS: We conducted an observational, retrospective cohort study in children with a diagnosis of IEI who underwent HSCT between 2007 and 2018. RESULTS: Forty-seven patients were identified, and 5 were re-transplanted. Sixty-eight percent were male. The median age at diagnosis was 0.6 years, and for HSCT was 1.4 years. The most common diseases were chronic granulomatous disease (38%) followed by severe combined immune deficiencies (19%) and hemophagocytic lymphohistiocytosis (15%). Cord blood donors were the most used source of HSCT (44%). T cell-replete grafts from haploidentical donors using post-transplantation cyclophosphamide represent 37% of the cohort. All patients received conditioning, 62% with a non-myeloablative regimen. Calcineurin inhibitors were the main graft-versus-host disease prophylaxis (63.8%). Acute graft-versus-host disease developed in 35% of the total patients. The most frequent post-transplant infections were viral and fungal infections. The 1-year overall survival rates for the patients who received HSCT from identical, haploidentical, and cord sources were 80%, 72%, and 63%, respectively. The 5-year overall survival was 63%. CONCLUSIONS: HSCT is a curative treatment option for some IEI and can be performed with any donor type. Early and timely treatment in referral centers can improve survival.

Hemophagocytic Lymphohistiocytosis in Patients With Primary Immunodeficiency.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.

Clinical Outcomes of COVID-19 Patients with Pre-existing, Compromised Immune Systems: A Review of Case Reports.

In the ongoing COVID-19 pandemic, all COVID-19 patients are naïve patients as it is the first-time humans have been exposed to the SARS-CoV-2 virus. As with exposure to many viruses, individuals with pre-existing, compromised immune systems may be at increased risk of developing severe symptoms and/or dying because of (SARS-CoV-2) infection. To learn more about such individuals, we conducted a search and review of published reports on the clinical characteristics and outcomes of COVID-19 patients with pre-existing, compromised immune systems. Here we present our review of patients who possess pre-existing primary antibody deficiency (PAD) and those who are organ transplant recipients on maintenance immunosuppressants. Our review indicates different clinical outcomes for the patients with pre-existing PAD, depending on the underlying causes. For organ transplant recipients, drug-induced immune suppression alone does not appear to enhance COVID-19 mortality risk - rather, advanced age, comorbidities, and the development of secondary complications appears required.

A retrospective description of primary immuno-deficiency diseases at Red Cross War Memorial Children's Hospital, Cape Town, South Africa, 1975 - 2017.

BACKGROUND: The primary immunodeficiency diseases (PIDs) constitute a diverse and ever-expanding group of inborn errors affecting a wide range of immune functions. They are not well documented in sub-Saharan Africa. OBJECTIVES: To describe the spectrum of PIDs at a tertiary paediatric hospital. METHODS: A retrospective descriptive study of PIDs diagnosed at Red Cross War Memorial Children's Hospital, Cape Town, South Africa (SA), between 1975 and 2017 was undertaken. RESULTS: We identified 252 children with PIDs, spanning eight of the nine categories listed in the 2017 classification of the International Union of Immunological Societies. Predominantly antibody deficiencies, combined immunodeficiencies with associated syndromic features, and immunodeficiencies affecting cellular and humoral immunity accounted for most children with PIDs (n=199, 79.0%). The mean age (standard deviation) at diagnosis was 46 (50) months, and the male/female ratio was 1.5:1. There was a history of parental consanguinity in 3 cases (1.2%). Recurrent infection was the most prevalent presenting phenotype, manifesting in 177 patients (70.2%). Genetic or chromosomal confirmation was obtained in 42/252 cases (16.7%). Common interventions used to prevent infection were antimicrobial prophylaxis and immunoglobulin replacement therapy, administered to 95 (37.7%) and 93 (36.9%) of the patients, respectively. Six of 7 children who underwent haematopoietic stem cell transplantation (HSCT) had successful outcomes. The 7th patient died 2 months after HSCT from overwhelming infection. Although we could not account for the children lost to follow-up during the study period, 53 deaths were confirmed (21.0%). CONCLUSIONS: Several challenges exist in the recognition and treatment of children with PIDs in our setting. These include limited access to genetic diagnostics and HSCT. Suboptimal treatment options contribute to the overall mortality of PIDs in SA.

Frequency and Manifestations of Autoimmunity Among Children Registered in the Kuwait National Primary Immunodeficiency Registry.

Objectives: To present a prospective report on the characteristics of autoimmune manifestations in patients with primary immunodeficient children registered in the Kuwait National PIDs Registry (KNPIDR). Methods: The data were obtained from the Kuwait National Primary Immunodeficiency Disorders Registry during the period of January 2004 to December 2019. Results: A total of 286 PID children were registered in KNPIDR during the study period with a predominance of immunodeficiencies affecting cellular and humoral immunity followed by combined immunodeficiencies with associated syndromic features and diseases of immune dysregulation. Fifty-seven (19.9%) patients presented with a total of 107 autoimmune manifestations. There was no significant statistical association between autoimmune manifestations and gender. Patients with autoimmune manifestations were older at onset of PID symptoms compared to those with no such manifestations, but this did not reach level of significance. The diagnosis delay was longer in patients with autoimmune manifestations compared to those with no such manifestations (p = 0.038). Forty-seven percent of these manifestations were among the presenting symptoms while 53% were documented later during the course of the disease. Fifty-seven percent of the patients developed 1 autoimmune manifestation, 30% developed 2 such manifestations, and 16% had ≥3 autoimmune manifestations. The most common autoimmune manifestation was cytopenia, followed by gastrointestinal manifestations and manifestations of the skin, hair, and nails. Autoimmune cytopenia were more common in patients with immune dysregulation syndromes, while gastrointestinal and skin manifestations predominate in patients with immunodeficiencies affecting cellular and humoral immunity and endocrine manifestations were more common in immune dysregulation syndromes. There were significant statistical associations between developing autoimmune manifestations and death as well as PID categories, being more common in patients with immune dysregulation. The frequency of autoimmunity was high among patients with RAG, WAS, STAT5b, NF-κB2, Fas, FasL, LRBA, APECED, IL-10, and C4 deficiencies. Conclusions: Autoimmunity is frequent in patients with PIDs in Kuwait. This should prompt the suspicion of a PID in patients who present initially with autoimmunity, especially autoimmune cytopenia. Such patients should be managed with extra care since they are at a higher risk of death.

Multicenter Outcome of Hematopoietic Stem Cell Transplantation for Primary Immune Deficiency Disorders in India.

Background: Hematopoietic stem cell transplantation (HSCT) is the curative option for many primary immune deficiency disorders (PID). In the last 5 years, increased awareness, availability of diagnostics based on flow cytometry, genetic testing, improved supportive care, use of reduced toxicity conditioning, and success of haploidentical donor HSCT have improved access to HSCT for children with PID in India. We present results on children with PID who underwent HSCT across India and the factors that influenced outcome. Patients and Methods: We collected retrospective data on the outcome of HSCT for PID from seven centers. We analyzed the impact of the type of PID, conditioning regimen, time period of HSCT- before or after January 2016, graft versus host disease prophylaxis, cause of mortality and overall survival. Results: A total of 228 children underwent HSCT for PID at a median age of 12 months (range, 1 to 220 months) with a median follow up of 14.4 months. Infants accounted for 51.3% of the cohort and the male female ratio was 3:1. SCID (25%) and HLH (25%) were the more frequent diagnoses. Matched family donor was available in 36.4% and 44.3% children had a haploidentical HSCT. Reduced and myeloablative conditioning regimens were used with 64% children receiving a treosulfan based conditioning regimen. Peripheral blood stem cells were the predominant graft source at 69.3%. The survival in infants (60.2%) was inferior to children aged over 1 year (75.7% p value = 0.01). Children with Wiskott Aldrich syndrome (74.3%) and chronic granulomatous disease (82.6%) had the best outcomes. The survival was superior in children receiving HSCT from a matched sibling (78%) versus an alternate donor HSCT (61% p value = 0.04). In the cohort transplanted after January 2016 survival improved from 26.8% to 77.5% (p value = 0.00). Infection remains the main cause of mortality at in over 50% children. The 5-year overall survival rate was 68%. Conclusion: Survival of children with PID undergoing HSCT in India has improved dramatically in last 5 years. Alternate donor HSCT is now feasible and has made a therapeutic option accessible to all children with PID.

Primary Immunodeficiency and Cancer in Children; A Review of the Literature.

The life span of patients with primary and secondary immunodeficiencies has increased due to recent advances in diagnostic and therapeutic strategies. Primary immune deficiencies (PIDs) are genetic disorders that predispose patients to frequent infections, autoimmunity and malignancies. Genomic instability due to defective DNA repair processes and other unknown mechanisms in patients with PID leads to an enhanced risk of cancer. PIDs were originally described as rare diseases occurring only in infants and young children, which are associated with severe clinical symptoms. However, advances in gene sequencing technologies, have revealed that they are much more common than originally appreciated and are present in older children, adolescents, and adults. After infection, malignancy is the most prevalent cause of death in both children and adults with PIDs. The overall risk of developing cancer in patients with PID is estimated to range from 4.7 to 5.7 percent. A 1.4 to 1.6-fold excess relative risk of cancer has been reported for PIDs. Increasing awareness among physicians regarding PID and cancer may lead to earlier diagnosis which may decrease morbidity and mortality. In this paper, we review the various categories of PIDs in children and highlight their association with various malignancies. MEDLINE was searched to identify articles for inclusion. Three authors have independently screened literature search results from MEDLINE and abstracted data from studies dealing with cancers of children among primary immune deficiencies.

A 30-Year Prospective Follow-Up Study Reveals Risk Factors for Early Death in Cartilage-Hair Hypoplasia.

Cartilage-hair hypoplasia (CHH) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy. Management of CHH is complicated by a paucity of long-term follow-up data, as well as knowledge on prognostic factors. We assessed clinical course and risk factors for mortality in a prospective cohort study of 80 patients with CHH recruited in 1985-1991 and followed up until 2016. For all patients we collected additional health information from health records and from the national Medical Databases and Cause-of-death Registry. The primary outcome was immunodeficiency-related death, including death from infections, lung disease and malignancy. Standardized mortality ratios (SMRs) were calculated using national mortality rates as reference. Half of the patients (57%, n = 46) manifested no symptoms of immunodeficiency during follow-up while 19% (n = 15) and 24% (n = 19) demonstrated symptoms of humoral or combined immunodeficiency, including six cases of adult-onset immunodeficiency. In a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. Of the 15 patients with non-skin cancer, eight had no preceding clinical symptoms of immunodeficiency. Altogether 20 patients had deceased (SMR = 7.0, 95%CI = 4.3-11); most commonly from malignancy (n = 7, SMR = 10, 95%CI = 4.1-21) and lung disease (n = 4, SMR = 46, 95%CI = 9.5-130). Mortality associated with birth length below -4 standard deviation (compared to normal, SMR/SMR ratio = 5.4, 95%CI = 1.5-20), symptoms of combined immunodeficiency (compared to asymptomatic, SMR/SMR ratio = 3.9, 95%CI = 1.3-11), Hirschsprung disease (odds ratio (OR) 7.2, 95%CI = 1.04-55), pneumonia in the first year of life or recurrently in adulthood (OR = 7.6/19, 95%CI = 1.3-43/2.6-140) and autoimmunity in adulthood (OR = 39, 95%CI = 3.5-430). In conclusion, patients with CHH may develop adult-onset immunodeficiency or malignancy without preceding clinical symptoms of immune defect, warranting careful follow-up. Variable disease course and risk factors for mortality should be acknowledged.

Myeloid malignancies with somatic GATA2 mutations can be associated with an immunodeficiency phenotype.

Germline mutations in GATA2 are associated with a complex immunodeficiency and cancer predisposition syndrome. Somatic GATA2mut in myeloid malignancies may impart a similar phenotype. We reviewed adult patients with a diagnosis of GATA2mut hematological malignancy who were referred to our HHMC for genetic testing, and identified to have somatic GATA2mut. Nine patients with a median age of 63 years were included. Six patients (66.7%) were males. Atypical CML and acute myeloid leukemia were the most common initial presentation. The median overall VAF was 47.14%. Monocytopenia was pronounced when the GATA2mut involved the C-terminal ZFD. GATA2 N-terminal ZFD mutations tend to be co-mutated with biCEBPAmut. Unlike germline GATA2 mutations, monocytopenia associated with somatic GATA2 mutations often resolved at remission. We concluded that similar to germline GATA2 mutations, a subset of somatic GATA2 mutations can impart a germline phenotype.

A New Conditioning Regimen Can Significantly Promote Post-Transplant Immune Reconstitution and Improve the Outcome of Umbilical Cord Blood Transplantation for Patients.

This study included data from 81 consecutively enrolled patients with hematological diseases who had been treated with unrelated umbilical cord blood transplantation (UCBT) between September 2014 and April 2019. All patients received intense conditioning regimens with combined fludarabine and high-dose cyclophosphamide (FC) before undergoing UCBT. Sixty-seven patients received a single UCBT, and 14 patients received a double UCBT. Fifty patients were pretreated with the fludarabine, busulfan, and cyclophosphamide (FBC) protocol, while 31 patients were treated with FC before transplantation. Graft-versus-host disease (GVHD) was prevented with cyclosporine A and mycophenolate mofetil administration. According to low-resolution, human leukocyte antigen (HLA) donor-recipient matching at six sites, 53 patients had 5-6 matches, while 28 patients had 4 matches. Seventy-eight patients (96.3%) achieved complete engraftment in this study. Thirty-six patients developed acute GVHD (aGVHD). The cumulative incidence of grade I-II aGVHD at day 100 posthematopoietic stem cell transplantation was 29.6%, and the cumulative incidence of grade III-IV aGVHD was 14.8%. At the end of the follow-up, 12 patients died due to treatment-related complications, and 4 died of disease relapse after transplantation. The transplant-related deaths were due to transplant-related infection (8 of 81), GVHD (2 of 81), and organ toxicity (2 of 81). The probability of overall survival (OS) was 80.2%. A higher dose of cyclophosphamide combined with fludarabine conditioning in UCBT was an effective curative method for treatment of hematologic disorders and could enhance the engraftment of umbilical cord blood stem cells, promote post-transplant immune reconstitution, and improve OS.