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X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II–IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55–86%) and 64% (CI 46–77%), respectively. Recipient and donor HLA mismatch and grade II–IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5–23.3, p = 0.01) and 8.2 (CI 2.1–32.7, p

Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

Alemtuzumab is used as part of reduced-intensity and reduced-toxicity transplant conditioning regimens for nonmalignant diseases. Prior studies identified an ideal target concentration range of 0.15-0.6 mcg/mL at day 0. However, only 24% of patients fall within this window using standard intermediate dosing. We performed a pilot study of a novel target concentration intervention strategy to target day 0 alemtuzumab concentrations to 0.15-0.6 mcg/mL. Twelve patients received model-informed alemtuzumab dosing of 0.5-0.6 mcg/kg divided over days -14 to -12. Alemtuzumab concentrations were measured, and pharmacokinetic (PK) modeling was performed on day -5 to predict day 0 concentrations. If the day 0 alemtuzumab concentration was predicted to fall below 0.15 mcg/mL, simulations were performed to identify the individual "top-up" dose needed to achieve the target day 0 concentration window. Six (50%) patients achieved day 0 alemtuzumab concentrations between 0.15 and 0.6 mcg/mL (4 received a top-up dose). Five patients had day 0 concentrations above the target window (no top-up doses). One patient had a day 0 concentration below the target range in the presence of anti-alemtuzumab antibodies. A concentration intervention strategy approach to alemtuzumab treatment can successfully target a greater proportion of patients into the ideal therapeutic window. Additional dose-reduction studies are needed to further optimize the initial dosing and achieve target attainment in all patients.

Aim Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A recently proposed therapeutic range of 0.15-0.6 μg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 pediatric and young adult patients (median age 6.4 years; range 0.28 - 21.4 years) with non-malignant disorders undergoing HCT. PK/PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103 /μL and 0.045μg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated optimal target achieving dose as allometry-based dose of 18 mg*(weight/70)0.75 or body surface area (BSA)-based dose of 10 mg/m2 , divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency due to mutations in any of the critical subunits of the phagocyte NADPH oxidase complex, resulting in impaired oxidase activity of neutrophils, monocytes, and tissue macrophages. It is characterized by increased susceptibility to recurrent and severe infections with a narrow pathognomonic spectrum of bacteria and fungi, granuloma formation, and inflammatory disease, primarily of the gastrointestinal tract, lungs, and liver. Inflammatory disease in CGD is difficult to predict and often refractory to therapy. Patients with CGD also have increased incidence of autoimmune disease, including lupus-like symptoms, sarcoidosis, IgA nephropathy, rheumatoid arthritis, and other autoimmune manifestations. With increasing awareness of disease, widespread use of antimicrobial prophylaxis, and advancements in hematopoietic stem cell transplantation (HSCT), outcomes have improved dramatically and many patients now live well into adulthood. HSCT is the only widely available definitive treatment for CGD with the potential for resolution of both infectious and inflammatory complications. Overall survival rates are now consistently near or >90% for pediatric patients less than 14 years regardless of donor source, and survival rates are improving for adolescents and young adults, including those with severe infection and/or uncontrolled inflammatory disease at time of transplantation. Early results from gene therapy trials have also demonstrated resolution of the CGD phenotype, although long-term outcomes with gene therapy are unknown.

Background Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease. Objective We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency. Methods Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry. Results A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease. Conclusions Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in any of the five subunits of the NADPH oxidase complex responsible for the respiratory burst in phagocytic leukocytes. Patients with CGD are at increased risk of life-threatening infections with catalase-positive bacteria and fungi and inflammatory complications such as CGD colitis. The implementation of routine antimicrobial prophylaxis and the advent of azole antifungals has considerably improved overall survival. Nevertheless, life expectancy remains decreased compared to the general population. Inflammatory complications are a significant contributor to morbidity in CGD, and they are often refractory to standard therapies. At present, hematopoietic stem cell transplantation (HCT) is the only curative treatment, and transplantation outcomes have improved over the last few decades with overall survival rates now > 90% in children less than 14 years of age. However, there remains debate as to the optimal conditioning regimen, and there is question as to how to manage adolescent and adult patients. The current evidence suggests that myeloablative conditioning results is more durable myeloid engraftment but with increased toxicity and high rates of graft-versus-host disease. In recent years, gene therapy has been proposed as an alternative to HCT for patients without an HLA-matched donor. However, results to date have not been encouraging. with negligible long-term engraftment of gene-corrected hematopoietic stem cells and reports of myelodysplastic syndrome due to insertional mutagenesis. Multicenter trials are currently underway in the United States and Europe using a SIN-lentiviral vector under the control of a myeloid-specific promoter, and, should the trials be successful, gene therapy may be a viable option for patients with CGD in the future.

Twenty-eight patients were maintained on subcutaneous immunoglobulin replacement for persistent B-cell aplasia and agammaglobulinemia following CD19-targeted chimeric antigen receptor T-cell therapy for B-cell lymphoblastic leukemia. Patients were transitioned from intravenous to subcutaneous immunoglobulin replacement at a median of 11.5 months (range, 4-20). Increasing serum IgG level was significantly associated with a lower rate of sinopulmonary infection (P = 0.0072). The median serum IgG level during infection-free periods was 1000 mg/dL (range, 720-1430), which was significantly higher than IgG levels in patients with sinopulmonary infections. As such, we recommend maintaining a goal IgG level > 1000 mg/dL to provide optimal protection.

IntroductionInflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.MethodsWe collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.ResultsForty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p = 0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p = 0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p = 0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p = 0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p = 0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2years following allogeneic HCT.ConclusionsIn this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34+ cell dose was 10.2 × 106/kg (range, 4.54 to 20 × 106/kg), and the median TCRαβ+ cell dose was 2.53 × 104/kg (range, 0 to 44.9 × 104/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology. Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3+, CD4+, and CD8+ T cells present on first assessment at 4 months post-HCT, and significant numbers of naive CD4+ T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ+ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.

Background Optimal graft versus host disease (GVHD) prophylaxis prevents severe manifestations without excess immunosuppression. Standard prophylaxis includes a calcineurin inhibitor (CNI) with low-dose methotrexate. However, single-agent CNI may be sufficient prophylaxis for a defined group of patients. Single-agent CNI has been used for GVHD prophylaxis for human leukocyte antigen (HLA)-matched sibling donor (MSD) bone marrow transplants (BMTs) in young patients at the Children's Hospital of Philadelphia for over 20 years. Here, we describe outcomes using this prophylactic strategy in a recent cohort. Procedure We performed a single-institution chart review and retrospective analysis of consecutive children undergoing MSD BMT who received single-agent CNI for GVHD prophylaxis between January 2002 and December 2014. Results Fifty-two children with a median age of 6.1 years (interquartile range [IQR] 2.5–8.3) and donor age of 6 years (IQR 3–10), with malignant and nonmalignant diseases (n = 35 and 17, respectively) were evaluated. Forty-three (82.6%) received oral prophylaxis with single-agent tacrolimus after initial intravenous therapy. Rates of GVHD were consistent with reported rates on dual prophylaxis: the overall incidence of grades 2–4 acute GVHD was 25.5%, grades 3–4 GVHD 9.8%, and chronic GVHD 10.4%. The cumulative incidence of relapse among children with malignancy was 20% at a median of 237 days (IQR 194–318) post-transplant. Two-year overall survival was 82.7% (95% confidence interval [CI]: 69.4–90.6%) and event-free survival was 78.9% (95% CI: 65.1–87.7%). No patient experienced graft failure. Conclusions Single-agent CNI is a safe, effective approach to GVHD prophylaxis in young patients undergoing HLA-identical sibling BMT. Additionally, single-agent oral tacrolimus is a reasonable alternative to cyclosporine in this population.

Background Alemtuzumab is frequently used as part of reduced-intensity and reduced-toxicity conditioning regimens. High alemtuzumab levels at day 0 are associated with decreased rates of acute graft-versus-host disease (aGVHD) but increased rates of mixed chimerism, viral reactivation and delayed immune reconstitution. Prior studies performed at our center identified an ideal therapeutic range of 0.15-0.6 mcg/mL at day 0. We aimed to determine if precision dosing of alemtuzumab is feasible in the pediatric HCT setting. Methods Twelve patients with non-malignant diseases were enrolled. Alemtuzumab was dosed, and levels were checked per the schema in Figure 1. Pharmacokinetic modeling was performed on Day -5 to predict Day 0 levels. If patients were predicted to fall below 0.15 mcg/mL, simulations were performed, and a top-up dose of alemtuzumab was given on Day -3. Conditioning also included fludarabine 150 mg/m2 or 5 mg/kg if Results Observed alemtuzumab level was within predicted range for 6 (50%) patients, and 6 (50%) patients were within the ideal therapeutic range (Figure 2). This is double the percent of patients within the ideal therapeutic range with traditional dosing (Figure 3). Four patients received a top-up dose of alemtuzumab on day -3. One patient developed acute cholecystitis, and conditioning was halted after alemtuzumab. The patient was included in alemtuzumab level analysis but excluded from clinical outcomes. Ten (91%) patients engrafted on median day +12 (range 10-15). One (9%) patient had primary graft failure with autologous neutrophil recovery and was successfully re-transplanted 8 months later. There was one (9%) case of Grade II aGVHD. Six (55%) patients had full (>95%) donor chimerism at day +100. Four (36%) patients with day 0 alemtuzumab levels ranging from 0.35-1.12 mcg/mL developed mixed chimerism (lowest chimerism 29.6-78.7% prior to Day +100). Three of these received CD34+ cell boosts, and one went on to second transplant. All 11 patients are alive and well at a median of 16 months (range 10-24) follow-up. Conclusions Our results confirm the feasibility of successful alemtuzumab precision dosing in HCT. Further dose de-escalation is needed to target the majority of patients to the goal range, and additional myelosuppression may decrease the incidence of mixed chimerism.

Differentiation-based therapeutics are an underutilized but a potentially significant treatment option for cancer patients. We show that lovastatin, a competitive inhibitor of the rate-limiting enzyme of mevalonate synthesis HMG-CoA reductase, is able to induce tumour cell differentiation and apoptosis in vitro. We used embryonal carcinoma (EC) and neuroblastoma (NB) cell lines and found that lovastatin promoted apoptosis and induced expression of the neuronal differentiation markers, tyrosine hydroxylase (TH), and growth-associated protein 43. The apoptotic and differentiation responses were time and dose-dependant and rescued by the co-administration of mevalonate. The expression of TH is regulated primarily by a cyclic AMP (cAMP) response element (CRE) in its promoter. Lovastatin enhanced the expression of a CRE-driven luciferase construct in P19 cells. Furthermore, combining lovastatin with 1 mM dibutyryladenosine 3′,5′-cyclic monophosphate treatments induced higher expression from the CRE construct, enhanced differentiation and cytotoxicity. This study suggests the potential of combining these therapeutic approaches in EC and NB patients.