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.
Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of ...life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality.
To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US.
This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon.
Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia.
The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy.
In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 MSD and $637 036 MUD) and generated similar QALYs (20.61 vs 17.25 MSD and 17.18 MUD). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses.
In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.
The Primary Immune Deficiency Treatment Consortium (PIDTC) is enrolling children with severe combined immunodeficiency (SCID) to a prospective natural history study. We analyzed patients treated with ...allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2014, including 68 patients with typical SCID and 32 with leaky SCID, Omenn syndrome, or reticular dysgenesis. Most (59%) patients were diagnosed by newborn screening or family history. The 2-year overall survival was 90%, but was 95% for those who were infection-free at HCT vs 81% for those with active infection (P = .009). Other factors, including the diagnosis of typical vs leaky SCID/Omenn syndrome, diagnosis via family history or newborn screening, use of preparative chemotherapy, or the type of donor used, did not impact survival. Although 1-year post-HCT median CD4 counts and freedom from IV immunoglobulin were improved after the use of preparative chemotherapy, other immunologic reconstitution parameters were not affected, and the potential for late sequelae in extremely young infants requires additional evaluation. After a T-cell–replete graft, landmark analysis at day +100 post-HCT revealed that CD3 < 300 cells/μL, CD8 < 50 cells/μL, CD45RA < 10%, or a restricted Vβ T-cell receptor repertoire (<13 of 24 families) were associated with the need for a second HCT or death. In the modern era, active infection continues to pose the greatest threat to survival for SCID patients. Although newborn screening has been effective in diagnosing SCID patients early in life, there is an urgent need to identify validated approaches through prospective trials to ensure that patients proceed to HCT infection free. The trial was registered at www.clinicaltrials.gov as #NCT01186913.
•Active infection pretransplant adversely impacts survival (81% in patients with active infection vs 95% in infection-free patients; P = .009).•Preparative chemotherapy improved 1-year post-HCT median CD4 counts (P = .02) and freedom from IV immunoglobulin (P < .001).
Background Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti-IgE medication omalizumab (Xolair; ...Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. Objective We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. Methods Thirty-seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1-day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. Results The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab-treated subjects versus 22.5 mg for placebo-treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo ( P < .01). Twenty-three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000-mg food challenge. Overall reaction rates were not significantly lower in omalizumab-treated versus placebo-treated subjects (odds ratio, 0.57; P = .15), although omalizumab-treated subjects were exposed to much higher peanut doses. Conclusion Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.
To the Editor: There has been increased appreciation in recent years that severe combined immunodeficiency (SCID) is not one disease, but rather a collection of genetic disorders that share a common ...phenotype of very low numbers and insufficient function of T lymphocytes, with variable deficiencies in B and natural killer cells.1 SCID may be screened for by determining the numbers of T-cell receptor excision circles on newborn dried blood spots, which will be low to absent.2,3 The introduction and now near-complete adoption of population-based newborn screening (NBS) for SCID in the United States has led to earlier diagnosis of both typical SCID and atypical, or leaky, forms of these diseases, the latter caused by hypomorphic gene defects that allow a small amount of gene function with a consequently varied spectrum of immune defects, including Omenn syndrome.4 Unique clinical features of particular genetic subtypes of SCID, such as increased sensitivity to radiation and alkylating chemotherapy in patients with Artemis/DCLRE1C deficiency, impact outcome following allogeneic hematopoietic cell transplantation (HCT) including survival, immune reconstitution, and late effects.1,5 The Primary Immune Deficiency Treatment Consortium (PIDTC) 6901 Prospective Study has been enrolling patients with SCID disorders in the United States and Canada since August 2010. A limitation of these data is that the PIDTC does not capture all infants with SCID diagnosed in the United States and Canada. Since August 2010, the 6901 protocol has enrolled a median of 37 eligible patients per year (range, 14-60 patients/y). Knowing gene distributions in the United States and Canada will be useful for scientists studying SCID, especially those planning trials of new gene-specific treatments, for example, correction of genes such as ADA, IL2RG, or DCLRE1C in autologous cells. ...SCID infants identified as neonates by screening are more likely than in previous times to be infection-free at diagnosis, offering the opportunity to observe genotype/phenotype correlations without confounding effects of infectious complications.
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.
Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by ...regulatory agencies.
We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product.
A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms.
Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs.
In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.
Newborn screening has led to a better understanding of the prevalence of Severe Combined Immunodeficiency (SCID) overall and in terms of specific genotypes. Survival has improved following ...hematopoietic stem cell transplantation (HCT) with the best outcomes seen following use of a matched sibling donor. However, questions remain regarding the optimal alternative donor source, appropriate use of conditioning and the impact of these decisions on immune reconstitution and other late morbidities. Areas covered: The currently available literature reporting late effects after HCT for SCID and use of alternative therapies including enzyme replacement, alternative donors and gene therapy are reviewed. A literature search was performed on Pubmed and ClinicalTrials.gov using key words 'Severe Combined Immunodeficiency', 'SCID', 'hematopoietic stem cell transplant', 'conditioning', 'gene therapy', 'SCID newborn screening', 'TREC' and 'late effects'. Expert commentary: Newborn screening has dramatically changed the clinical presentation of newborn SCID. While the majority of patients with SCID survive HCT, data regarding late effects in these patients is limited and additional studies focused on genotype specific late effects are needed. Prospective studies aimed at minimizing the use of alkylating agents and reducing late effects beyond survival are needed. Gene therapy is being developed and will likely become a more commonly used treatment that will require separate consideration of survival and late effects.
Summary
Viral infections are a serious cause of morbidity and mortality following haematopoietic stem cell transplantation (HSCT). Adoptive cellular therapy with virus‐specific T cells (VSTs) has ...been successful in preventing or treating targeted viruses in prior studies, but the composition of ex vivo expanded VST and the critical cell populations that mediate antiviral activity in vivo are not well defined. We utilized deep sequencing of the T‐cell receptor beta chain (TCRB) in order to classify and track VST populations in 12 patients who received VSTs following HSCT to prevent or treat viral infections. TCRB sequencing was performed on sorted VST products and patient peripheral blood mononuclear cells samples. TCRB diversity was gauged using the Shannon entropy index, and repertoire similarity determined using the Morisita–Horn index. Similarity indices reflected an early change in TCRB diversity in eight patients, and TCRB clonotypes corresponding to targeted viral epitopes expanded in eight patients. TCRB repertoire diversity increased in nine patients, and correlated with cytomegalovirus (CMV) viral load following VST infusion (P = 0·0071). These findings demonstrate that allogeneic VSTs can be tracked via TCRB sequencing, and suggests that T‐cell receptor repertoire diversity may be critical for the control of CMV reactivation after HSCT.
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