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Evidence Review Workgroup Advisory Committee on Heritable Disorders in Newborns and Children Report November 2008 James M. Perrin, MD Professor of Pediatrics, Harvard Medical School Director, MGH Center for Child and Adolescent Health Policy Current Progress and Activities Pompe Disease – Final report submitted SCID – Discussion today Krabbe Disease – Review in process SCID Report Key authors: – Ellen Lipstein, MD – Alix Knapp, MS Program director: – James M. Perrin, MD Staff: – Marsha Browning, MD, MPH – Alex R. Kemper, MD, MPH, MS – Nancy Green, MD – Lisa Prosser, PhD – Denise Queally, JD – Jennifer DeZarn, BA – Sienna Vorono, BA Severe Combined Immunodeficiency (SCID) Group of disorders characterized by absence of both humoral and cellular immunity Severe defect in T cell production and function, with additional defects in B-lymphocytes and/or NK cells depending on the mutated gene At least 15 genes cause SCID when mutated As protection from maternal antibodies wanes, infants with SCID develop infections due to both common and opportunistic pathogens Rationale for Review Without treatment SCID leads to death in early childhood Earlier treatment, particularly before the onset of lung infection, may decrease mortality and morbidity associated with SCID and with treatment Methods to screen infants for SCID using quantitative PCR for T-cell receptor excision circles (TREC) have been developed Methods of Review Systematic literature review, summarizing the evidence available from published studies Assessment of critical unpublished data and data presented at meetings from key investigators Key Review Questions Incidence/prevalence Natural history – Timing of clinical onset – Severity of disease and variations – Genotype/phenotype Screening – – – – Methods of screening Accuracy of screening; sensitivity/specificity Methods of diagnosis Risks and costs Key Review Questions II Treatment – Methods – Does treatment help? – Does early treatment help? – Availability – Risks and costs Critical information still needed Materials Provided/Available Draft review summary Evidence table/abstracted articles Bibliography of all identified articles List of interviewees Systematic Review January 1988- October 2008: Medline, OVID In-Process and Other Non-Indexed Citations database – English language only – Human studies only – Eliminated: non-human data, reviews, editorials or other opinion pieces, case-series of <4 patients, only contained adult subjects or not addressing one or more of the key questions – References also from nomination form, reviews 725 abstracts selected for initial review 60 articles selected for review and abstraction Quality assessment directed toward study design Papers Meeting Review Criteria Study Design Number of papers Experimental intervention 0 Cohort study 11 Case-control study 8 Case series total 38 Sample size ≤ 10 11 Sample size 11 to 50 18 Sample size ≥ 51 9 Economic Evaluation 1 Other design 2* Total 60 *Epidemiologic studies using retrospective record review (Jones et al. 1991) and telephone survey (Boyle & Buckley, 2007) Additional Expert Communication Determined by literature review, discussion with genetic experts Included experts representing all major issues related to SCID Experts Contacted Mei Baker - Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin; Newborn Screening Program, Wisconsin State Laboratory of Hygiene Tony (Francisco) Bonilla - Harvard Medical School and Children’s Hospital, Boston, Mass Rebecca Buckley -Duke University Medical Center, Durham, North Carolina Anne Comeau -Deputy Director New England Newborn Screening Program University of Massachusetts Lisa Filipovich -Cincinnati Children's Hospital Medical Center Alain Fischer -Pediatric Immunology Department and the INSERM Research Unit Alan P. Knutsen -Pediatric Clinical Immunology Laboratory, St Louis University Health Sciences Center Ronald Laessig -Population Health Sciences and Pathology, University of Wisconsin Edward McCabe -Clinical Biochemical Genetics, Department of Pediatrics, Mattel Children’s Hospital at UCLA Sean McGhee -Division of Pediatric Immunology, David Geffen School of Medicine at UCLA Luigi Notarangelo -Division of Immunology, Children's Hospital Boston, Harvard Medical School Hans Ochs -Pediatrics and Immunology, University of Washington Sung-Yun Pai - Harvard Medical School and Children’s Hospital, Boston, Mass Ken Pass -Molecular Medicine, New York State Department of Health, Albany, New York Jennifer Puck -Department of Pediatrics, Institute for Human Genetics University of California, San Francisco Robert Vogt -Centers for Disease Control and Prevention, Newborn Screening Quality Assurance Program, Atlanta, Georgia Incidence Chan/Puck 2005 – 1:105,000 live births Extrapolation from XSCID samples sent to single lab Stephan et al., 1993 – 1:100,000 live births Based on 5 years of referrals to specialized units in France Jones et al., 1991 – 52/100,000 births in Navajo families Quality Assessment of Abstracted Natural History Literature Genotype/Phenotype Correlation 12 Data from retrospective screening studies in U.S. or similar population. 0 Data from systematic studies other than whole population screening. 5 Estimated from the known clinical features of the condition as described for individual cases or short series. 7 Incidence (cases per 100,000), average within the U.S. 4 Data obtained from whole-population screening or comprehensive national surveys of clinically detected cases. 1 Ia. As in I but more limited in geographical coverage or methodology. 2 Extrapolated from class I data for non-U.S. populations. 0 Estimated from number of cases clinically diagnosed in U.S. 1 Adapted from Pandor et al. 2004, Pollitt et al. 1997 Natural History Except for children diagnosed early in life, because of affected sibling, most children are diagnosed after recurrent (pulmonary) infections All SCID subtypes exhibit infection with opportunistic organisms, although timing of onset may vary Without treatment of underlying immunodeficiency, children with SCID die in early childhood from infection Known phenotype/genotype differences do not affect main findings related to infection and death Quality Assessment of Abstracted Screening Test Characteristic Literature Overall sensitivity and specificity of screening & false-positive rate 3 Data obtained from screening programs in U.S. population or similar. 0 Data from systematic studies other than from whole population screening. 3 Estimated from the known biochemistry of the condition. 0 Repeat specimen rate 0 Data obtained from screening programs in U.S. population or similar. 0 Data from systematic studies other than whole population screening. 0 Estimated from the known biochemistry of the condition. 0 Second-tier testing 1 Data obtained from screening programs in US population or similar. 0 Data from systematic studies other than whole population screening. 1 Estimated from the known biochemistry of the condition. 0 Adapted from Pandor et al. 2004, Pollitt et al. 1997 Main Screening Methods Whole blood lymphocyte counts Quantitative polymerase chain reaction Enzyme-linked immunosorbent assay (ELISA) of dried blood spots Screening Test Study Population Screening Methods Accuracy of Screen; Sens/Spec. Chan, Puck 2005 23 children with SCID 2 children with non-SCID immunodeficiencies 242 anonymized newborn screening cards DNA amplification of TREC from dried blood spot Among children known to have SCID, none had detectable levels of TREC and all had detectable β-actin. 2 children with non-SCID immunodeficiency had detectable TREC. *False positive rate: 1.5% from routine nurseries; 5% from special-care nurseries. ^Sensitivity: 84%-100% ^Specificity: 97-97.1% Hague et al. 1994 135 total children: 45 with SCID; 90 without First available lymphocyte count; cut-off of 2.8x109/l indicates SCID Children with SCID had significantly lower levels of lymphocytes. Unlike the 5 control children with low lymphocyte count, low lymphocyte count persisted in children with SCID *False-positive rate: 8% ^Sensitivity: 86.3%, and ^Specificity: 94.4% Hennewig et al. 2007 36 children with rotavirus gastroenteritis; 18 with SCID 18 without SCID Lymphocyte study SCID children more likely to have low WBC count:10/18 vs. 0/18, eosinophilia: 12/18 vs. 0/18 relative lymphopenia: 17/18 vs. 10/18 absolute lymphopenia:16/18 vs. 4/18 ^Sensitivity: 55.6% to 94.4% ^Specificity: 44.4% to 100%. 13 children with SCID 183 anonymized dried blood spots, presumed to be from children without SCID Dried blood spot study Evaluated 2-tiered screening approach first measuring IL-7 and then TREC only those with elevated IL-7 *Combined specificity of 100% (confidence interval, 97-100%) *Combined sensitivity of at least 85% McGhee et al. 2005 (Second-tier testing) *Calculation stated in article ^Our calculation using data provided in article Wisconsin Screening Experience Number Screened: 47,250 (01/01/2008-08/31/2008) Abnormal Results: 20 o Premature (<37 weeks) 11 (0.023%) o Full term 9 (0.019%) Inconclusive Results 76 o Premature (<37 weeks) 57 (0.121%) o Full term 19 (0.040%) Abnormal Results: Inconclusive Results: 1 DiGeorge Syndrome 1 Downs Syndrome with sepsis at birth 1 Idiopathic T-cell lymphopenia 1 Leukocyte migration defect 4 normal Flow Cytometry results 9 normal results on repeated newborn screening 2 pending cases 1 expired case 1 DiGeorge Syndrome 59 normal results on repeated newborn screening 2 pending cases 14 expired cases Courtesy of Dr. Mei Baker, presented at the Newborn Screening Symposium, November 2008 Treatment Methods Over the last twenty years, three modes of treatment for SCID have been investigated: – Allogeneic hematopoietic stem cell transplant (HSCT) including bone marrow transplant (BMT) – Enzyme replacement therapy (ERT) for some patients with ADA-deficient SCID – Small trials of gene therapy Quality Assessment of Abstracted Treatment Literature Effectiveness of treatment 47 I. Well-designed RCTs. 0 II-1. Well-designed controlled trials with pseudorandomization or no randomization. 0 II-2. Well-designed cohort studies: 8 A. prospective with concurrent controls 0 B. prospective with historical control 1 C. retrospective with concurrent controls. 7 II-3. Well-designed case-control (retrospective) studies. 0 III. Large differences from comparisons between times and/or places with and without intervention 4 IV. Opinions of respected authorities based on clinical experience, descriptive studies and reports of expert committees. 35 Adapted from Pandor et al. 2004, Pollitt et al. 1997 Does Treatment for SCID Help? Efficacy of HSCT over time: Large case-series Study Population Significant Findings Quality of Evidence Buckley et al. 1999 Case series 89 children treated with HSCT between 1982 and 1998 72 (81%) survived to follow-up (median follow-up 5.6 years) HLA-identical transplant from a related donor: 12/12 (100%) survived T-cell depleted haplo-identical: 60/77 (78%) survived Survival not statistically related to genotype Survival varied by race (white more likely to survive) and gender (all girls survived) 36 children developed GVHD; most cases of GVHD required no treatment. IV Stephan et al. 1993* Case series 117 patients treated for SCID between 1970 and 1992; 85 with bone marrow transplant HLA-identical transplant from a related donor 21/25 (84%) survived) Pheno-identical transplant (HLA genotypically haplo-identical) from related donor 2/5 (40%) survived HLA haplo-identical transplant without T-cell depletion 0/5 (0%) survived T-cell depleted haplo-identical transplant 28/50 (56%) survived 22 children did not receive any type of transplant and died 10 received fetal liver transplant, 9 died post transplant IV van Leeuwen et al. 1994 * Case series 31 patients between the ages of 1-94 months; BMT HLA-identical related: 6/10 (60%) survived HLA haplo-identical related: 9/19 (47%) survived HLA-matched unrelated: 0/2 (0%) survived IV * Potential patient overlap with Stephan et al. 1993 and van Leeuwen et al. 1994 Does Treatment for SCID Help? Survival after HSCT: Long-term follow-up Study Population Significant Findings Quality of Evidence Antoine et al. 2003; Fischer et al. 1990 Cohort study 475 patients (566 transplants) from 37 European centers; 1968 to 1999 Three-year survival with sustained engraftment was 77% for HLAidentical and 54% for HLA-non-identical transplants Survival has improved over time for both HLA-identical and HLA-nonidentical transplant recipients SCID phenotype was not associated with difference in survival Lung infection before HSCT and absence of a protective environment significantly affected outcome II-2 C, IV Cavazzan a-Calvo et al. 2007 Case series 31 children 10-27 years post-transplant: focus on factors associated with longterm T-cell reconstitution Myeloablation patients more likely to have evidence of donor-derived granulocytes and persistent naïve T-cells, as measured by TREC. 60% of TREC+ and 45% of TREC- had no clinical manifestations, at average follow-up in the TREC+ group was 13 years and in the TREC- was 16 years IV Friedrich, Honig & Muller 2007 Cohort study 7 children with SCID receiving HLA-identical transplant, 25 with HLA-haploidentical transplant, all at least 10 years out from transplant 3 patients’ T-cell numbers were decreased 4 patients’ PHA responses were decreased (all in HLA-haploidentical group and no chemotherapy) HLA-haploidentical with no conditioning had lower levels of naïve CD4+ cells and impaired B cell functioning IV Does Treatment for SCID Help? Additional Long-term follow-up studies Study Population Significant Findings Quality of Evidence Gennery et al. 2001 Case series 19 children treated from 1987-1998 using CAMPATH1MT depleted BMT for SCID 19/30 children survived longer than 1 year post-BMT Most deaths attributed to pre-existing infection 17 had normal immune function following transplantation IV Haddad et al. 1998 Case series 193 patients from 18 European centers between 1982 and 1993: focus on immune reconstitution 116 alive with evidence of engraftment 5 months after BMT. 24 later died (20%) T-cell function improved during the 2 years after BMT and continued to be better than B-cell function Poor outcomes associated with: absence of T-cell reconstitution, presence chronic GVHD 6 months after transplant, B- SCID (multivariate analysis) At last follow up (median, 6 years after transplant), 93% had normal Tcell function and 68% had normal B-cell function IV Slatter et al. 2008 Cohort study 36 children treated with BMT with depletion of T-cells from non-identical donor No significant survival difference between children receiving transplants depleted using anti-CD52 or anti-CD34 antibodies 5 patients in the anti-CD52 group and 2 in anti-CD34 group had GvHD II-2 C Does Early Treatment Help? Efficacy of HSCT in neonates/infants Study Quality of Evidence Population Significant Findings 21/22 (95%) infants alive at follow-up 51/67 (76%) who received transplants at 3.5 months or older survived to follow-up Median follow-up 5.6 years (range 3 months -16.5 years) IV Case series 22 infants transplanted prior to 3.5 months of life 67 infants transplanted later than 3.5 months of life Kane et al. 2001 13 children transplanted between 7 and 68 days-old All patients alive and well 0.5-11.5 years post-transplant (median 3 years). children required more than one transplant All children achieved neutrophil engraftment and normal levels of IgA, 7 have normal IgG, 12 have normal IgM 10/12 maintained normal development, of the other two: 1/12 has developmental problems and 1/12 has motor delay IV 21 children transplanted prior to 28 days of life (early treatment) 96 children transplanted at a median age of 190 days (range 45-516) (late treatment) 20/21 (95%) early treatment children survived One ADA-deficient patient died of CMV despite successful engraftment 71/96 (74%) late treatment children survived Mean time to significant T-cell function in all early treatment was 33 days and to normal T-cell function was 103 days Mean TREC value peaked earlier post-transplant for early treatment recipients but the 2 groups were indistinguishable by 5 years II-2 C Buckley et al. 1999* Case series Myers et al. 2002* Cohort study * Potential patient overlap of Myers et al. 2002, Buckley et al. 1999 Early Treatment for SCID 161 SCID infants transplanted over the past 26 years, overall survival rate of 125/161 (78%) Graph 1B. Transplanted after First 3.5 Months of Life Kaplan Meier Plot of 113 SCIDs Transplanted at Duke University Graph 1A. Transplanted in First 3.5 Months of Life Medical Center after the First 3.5 Months of Life 100 100 90 90 80 80 70 70 Percent Surviving Surviving Percent Percent Surviving Kaplan Meier Plot of 48 SCIDs Transplanted at Duke University Medical Center in the First 3.5 Months of Life 60 50 40 30 60 50 40 30 20 20 survival rate 96% 10 survival rate 71% 10 0 0 2 4 6 8 10 12 14 16 18 Years Post-Transplantation Years Post-Transplantation 20 22 24 26 0 0 2 4 6 8 10 12 14 16 Years Post-Transplantation Years Post-Transplantation The Kaplan-Meier graphs from Dr. Buckley (with permission) 18 20 22 24 26 Treatment for SCID: Availability From SCID expert interviews: – Dr. Buckley reports there are fifteen major and 34 minor centers in the U.S. and Canada currently performing stem cell transplantation for SCID. – Dr. Notarangelo, Bonilla, and Pai stated that an informal survey performed under the auspices of the NIAID/Rare Diseases workshop identified 34 centers in the United States and Canada that currently perform HCT for SCID Harms and Cost-effectiveness Screening and Diagnosis – No studies identified Diagnosis – None identified Treatment (2 studies) – 8/41 children undergoing HSCT developed auto-immune hemolytic anemia; 3 died from complications – 4 children (of the 9/10 who had successful gene therapy) developed leukemia between 30 and 68 months after gene therapy. 3/4 were successfully treated with chemotherapy and regained poly-clonal T-cell populations Cost-effectiveness (1 study) – Using a deterministic decision-tree model, comparing universal and targeted screening approaches, the authors assessed the thresholds at which screening would be cost-effective from a health care system perspective. Study reported, at a threshold of $100,000 per quality adjusted life year, an 86% likelihood of screening being cost-effective Summary Key findings: – SCID affects at least 1/100,000 newborns in the US – Several population-based screening trials are underway (Wisconsin) or planned; to date no population-based screening trial has been completed – Without curative treatment, newborns develop severe, often opportunistic, infections which lead to early death – Treatment, most commonly with hematopoietic stem cell transplant, decreases morbidity and mortality associated with SCID – Some evidence supports the notion that earlier treatment may lead to better outcomes Critical Needed Information Prevalence of SCID – A systematic method of case finding is needed in order to determine prevalence accurately. The new consortium of treatment centers (USIDNET) may serve as a method of more systematic case-finding. Accuracy of Screening – Initial pilot screening data from Wisconsin suggest that a relatively low false-positive rate. However, current data are limited. – Data regarding the accuracy of other screening methods in population-based protocols, are not available Feasibility of Screening – Wisconsin’s experience provides at least pilot data re feasibility. Data are needed regarding the ability of other newborn screening laboratories to offer SCID screening Critical Needed Information Acceptability of Screening – No data describe consumer or physician acceptance of newborn screening for SCID Is the evidence for early treatment enough? Cost-effectiveness (of screening and treatment) – Cost-effectiveness analyses utilizing measured costs and utilities, as well as applicable sensitivity analyses, are needed Adequacy of available treatment centers – No current data address variation in treatment success among centers or the number of centers in the United States and their capacity to provide treatment for SCID. Data from USIDNET and CIBMTR may, in the future, provide evidence on this topic Thank you