ABSTRACT
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.
Subject(s)
Graft vs Host Disease , Granulomatous Disease, Chronic , Hematopoietic Stem Cell Transplantation , Humans , Granulomatous Disease, Chronic/genetics , Granulomatous Disease, Chronic/therapy , Retrospective Studies , Prospective Studies , Transplantation, Homologous , Hematopoietic Stem Cell Transplantation/adverse effects , Genotype , Transplantation Conditioning/adverse effects , Graft vs Host Disease/prevention & controlABSTRACT
BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18. METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency , Humans , Infant, Newborn , Hematopoietic Stem Cell Transplantation/methods , Longitudinal Studies , Neonatal Screening , Proportional Hazards Models , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/therapy , Severe Combined Immunodeficiency/geneticsABSTRACT
BACKGROUND: Shearer et al in 2014 articulated well-defined criteria for the diagnosis and classification of severe combined immunodeficiency (SCID) as part of the Primary Immune Deficiency Treatment Consortium's (PIDTC's) prospective and retrospective studies of SCID. OBJECTIVE: Because of the advent of newborn screening for SCID and expanded availability of genetic sequencing, revision of the PIDTC 2014 Criteria was needed. METHODS: We developed and tested updated PIDTC 2022 SCID Definitions by analyzing 379 patients proposed for prospective enrollment into Protocol 6901, focusing on the ability to distinguish patients with various SCID subtypes. RESULTS: According to PIDTC 2022 Definitions, 18 of 353 patients eligible per 2014 Criteria were considered not to have SCID, whereas 11 of 26 patients ineligible per 2014 Criteria were determined to have SCID. Of note, very low numbers of autologous T cells (<0.05 × 109/L) characterized typical SCID under the 2022 Definitions. Pathogenic variant(s) in SCID-associated genes was identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of leaky/atypical SCID; there were 13 other rare genotypes. Patients with leaky/atypical SCID were more likely to be diagnosed at more than age 1 year than those with typical SCID lacking maternal T cells: 20% versus 1% (P < .001). Although repeat testing proved important, an initial CD3 T-cell count of less than 0.05 × 109/L differentiated cases of typical SCID lacking maternal cells from leaky/atypical SCID: 97% versus 7% (P < .001). CONCLUSIONS: The PIDTC 2022 Definitions describe SCID and its subtypes more precisely than before, facilitating analyses of SCID characteristics and outcomes.
Subject(s)
Severe Combined Immunodeficiency , Infant, Newborn , Humans , Infant , Severe Combined Immunodeficiency/diagnosis , Severe Combined Immunodeficiency/genetics , Retrospective Studies , Prospective Studies , Homeodomain Proteins/geneticsABSTRACT
BACKGROUND: Parvovirus B19 (PVB19) infection has been implicated in allograft failure or dysfunction in solid organ transplantation (SOT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the literature is limited. CASE: Two pediatric patients were diagnosed with PVB19 infection around the time of allo-HSCT graft failure. Both cases were secondary graft failure and required second allo-HSCT. CONCLUSION: There are many risk factors and potential confounders in determining the exact etiology of graft failure after allo-HSCT. These two cases highlight the importance of including PVB19 in the diagnostic evaluation for graft failure. PVB19 infection may be an important risk factor for allo-HSCT graft failure.
Subject(s)
Graft Rejection/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Parvoviridae Infections/etiology , Adolescent , Humans , Infant , Male , Parvovirus B19, Human , Risk FactorsABSTRACT
We report a case of myelodysplastic syndrome (MDS) occurring in an African American boy with Gorlin syndrome with a novel PTCH1 mutation. Before developing MDS, the patient had been treated with chemotherapy and radiation for a medulloblastoma. He received a bone marrow transplant for the MDS and eventually died of treatment complications. Secondary hematologic malignancies are a known complication of certain chemotherapeutics, although whether a patient with Gorlin syndrome has a greater propensity for the development of such malignancies is unclear.
Subject(s)
Basal Cell Nevus Syndrome/complications , Myelodysplastic Syndromes/etiology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Basal Cell Nevus Syndrome/therapy , Bone Marrow Transplantation , Child , Fatal Outcome , Humans , Male , Mutation , Myelodysplastic Syndromes/therapy , Patched-1 Receptor/geneticsABSTRACT
Reduced-intensity conditioning (RIC) before hematopoietic stem cell transplantation (HCT) in children could result in fewer complications during follow-up compared with myeloablative regimens. Hence, many RIC regimens are under investigation, but long-term follow-up is essential. We describe late follow-up beyond 2 years post-HCT in 43 children with nonmalignant disorders who underwent related or unrelated donor (56%) HCT on a multicenter study using a RIC regimen (alemtuzumab, fludarabine, and melphalan) followed by bone marrow (n = 30), peripheral blood (n = 3), or umbilical cord blood (n = 10) HCT for immune dysfunction, bone marrow failure, metabolic disorders, or hemoglobinopathy. Recipients (median age, 7.5 years; range, 3 to 26) underwent HCT 2 to 8 years (median, 3.1 years) before this report. Full donor (67%) or stable mixed chimerism (33%) was noted without late graft rejection. Five patients (12%) required systemic immunosuppression therapy (IST) beyond 2 years post-HCT for graft-versus-host disease (GVHD); 2 patients died 38 and 79 months later, whereas the others improved, enabling an IST wean. Overall, 17 complications were documented in 10 patients (23%). Complications not related to GVHD included hypothyroidism (n = 2), low grade neoplasms (n = 2), and delayed puberty (n = 1). One patient with GVHD had ovarian failure; all other postpubertal females resumed normal ovarian function. Twenty-seven of 28 school-age recipients were functioning at grade level. RIC HCT recipients thus had few regimen-related toxicities during long-term follow-up. However, objective long-term follow-up is still necessary to identify complications so timely intervention may be planned.
Subject(s)
Alemtuzumab/therapeutic use , Bone Marrow Transplantation/methods , Myeloablative Agonists/therapeutic use , Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adolescent , Adult , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/mortality , Child , Child, Preschool , Female , Follow-Up Studies , Graft Survival , Hemoglobinopathies/mortality , Hemoglobinopathies/therapy , Humans , Male , Melphalan/administration & dosage , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/mortality , Survival Analysis , Transplantation Conditioning/adverse effects , Transplantation Conditioning/mortality , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Young AdultABSTRACT
Single fraction total body irradiation (SFTBI) as part of a myeloablative preparative regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies was shown to have similar survival compared with fractionated total body irradiation (FTBI)-containing regimens, with less acute toxicity. The objective of this study was to determine long-term toxicity >2 years following SFTBI-based HSCT. Twenty-one patients were evaluated at a median follow-up of 6.8 years. Thyroid dysfunction was found in 21% of patients, 1 of whom (5.2%) was symptomatic; 23% had gonadal failure; 50% of patients with growth potential had linear growth disturbance; 27% had mild to moderate pulmonary disease; and 25% had cataracts. Intelligence quotient was stable. cGVHD was present in 28%, and 4 patients (19%) were on immune suppression 2 years posttransplant. Overall survival subsequent to 2 years posttransplant was 76% in this cohort of patients. No secondary malignancies were observed. In conclusion, the toxicities of SFTBI occurred at similar or reduced frequency compared with FTBI. SFTBI should be considered for patients who may benefit from a radiation-containing HSCT preparative regimen.
Subject(s)
Cyclophosphamide/adverse effects , Graft vs Host Disease/etiology , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Whole-Body Irradiation/adverse effects , Adolescent , Adult , Antineoplastic Agents, Alkylating/adverse effects , Child , Child, Preschool , Combined Modality Therapy , Female , Follow-Up Studies , Graft vs Host Disease/diagnosis , Graft vs Host Disease/mortality , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Humans , Infant , Male , Prognosis , Survival Rate , Transplantation Conditioning , Transplantation, Homologous , Young AdultABSTRACT
PURPOSE: The use of medical students as standardized patients in a performance assessment of pain evaluation was studied. METHODS: Fifty-two pairs of second-year medical students participated. One student portrayed a patient presenting with cancer pain and was interviewed by the other medical student. The student-patient then rated the interview using a checklist of pain assessment and general interviewing skills. The interviews were audiotaped and also rated independently. RESULTS: Based on student-patient ratings, 36 (69%) students demonstrated 9 or more of the 11 pain-specific checklist items, compared to 34 (65%) students according to the trained rater. Highly specific pain-related items had higher agreement than broader interviewing skill items. There would be differences in the summary assessments of students depending on which rating data were used. DISCUSSION: Medical students represent a readily accessible resource as patients for clinical simulations. Students tended to overestimate the performance of fellow students, but acting as a standardized patient had educational value, and can be used to extend simulated patient encounters within the curriculum. Further investigation is needed to improve the reliability of the feedback provided by student-patients.