Bio


I joined Stanford University in 2015 as a Clinical Professor of Pediatrics in the Division of Hematology/ Oncology, Stem Cell Transplantation and Regenerative Medicine, having completed my training in Pediatric Hematology/ Oncology at Childrens Hospital Los Angeles. My areas of clinical expertise have been in the areas of transplantation for immune deficiencies and immune reconstitution post HSCT. I have been actively involved with the care and treatment of children with primary immune deficiencies and work with the Primary Immune Deficiencies Consortium (PIDTC). I am very interested in cellular therapies as a treatment modality for rare genetic diseases. I currently am the PI for several gene therapy trials at Stanford for various disorders including cerebral adrenoleukodystrophy (cALD), Sickle Cell Anemia, Thalassemia and Pyruvate Kinase Deficiency. My other main areas of research have been in studying the late effects of patients following stem cell transplantation, in specific the neurocognitive function post HSCT. I have been involved with several national committees addressing the late effects of HSCT within the ASBMT and COG.

In addition to my research work in stem cell transplantation, I have been actively involved with mentorship and graduate medical education. I am currently the Program Director for the Hematology/ Oncology Fellowship and serve as a mentor through the Pediatric Mentoring Group.

Clinical Focus


  • Pediatric Hematology-Oncology
  • Pediatric Stem Cell Transplantation

Administrative Appointments


  • Program Director, Pediatric Stem Cell Transplantation Fellowship (2022 - Present)
  • Program Director, Pediatric Stem Cell Transplantation Fellowship (2022 - Present)
  • Program Director, Pediatric Hematology/ Oncology Fellowship, Stanford School of Medicine (2021 - Present)
  • Associate Program Director Pediatric Hematology/ Oncology Fellowship, Stanford School of Medicine (2020 - 2021)
  • Quality Director of the Bass Center, Lucile Packard Childrens Hospital (2015 - 2021)

Honors & Awards


  • Laura Bachrach Faculty Mentoring Award, Stanford University, Lucile Packard Children's Hospital (2019)

Boards, Advisory Committees, Professional Organizations


  • Medical Advisory Board, Make A Wish Greater Bay Area (2020 - Present)
  • Board Member, Make A Wish Greater Los Angeles (2010 - 2013)
  • Medical Advisory Committee, Ronald McDonald House (2018 - Present)

Professional Education


  • Fellowship: Childrens Hospital Los Angeles Pediatric Residency (1996) CA
  • Residency: Childrens Hospital Los Angeles Pediatric Residency (1993) CA
  • Internship: Childrens Hospital Los Angeles Pediatric Residency (1991) CA
  • Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (2000)
  • Medical Education: University of North Carolina Chapel Hill (1990) NC

Clinical Trials


  • A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD) Recruiting

    The purpose of this study is to evaluate the efficacy and safety of Lenti-D Drug Product (also known as elivaldogene autotemcel or Skysona, hereafter referred to as eli-cel) after myeloablative conditioning with busulfan and fludarabine in participants with CALD. A participant's blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the participant following myeloablative conditioning. Enrollment and treatment in Study ALD-104 have been completed and further enrollment in this study is not expected, although participants follow-up remains ongoing.

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  • A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease Recruiting

    This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects with severe sickle cell disease (SCD). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.

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  • A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia Recruiting

    This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects with transfusion-dependent β-thalassemia (TDT). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.

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  • Gene Therapy for Pyruvate Kinase Deficiency (PKD) Recruiting

    This is an open-label Phase I trial to evaluate the safety of a hematopoietic cell-based gene therapy for patients with Pyruvate Kinase Deficiency (PKD).

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  • Long Term Effects On Recipients of Hematopoietic Stem Cell Transplantation Recruiting

    This project allows for the systematic collection and analysis of long-term follow-up clinical parameters in children who have received a stem cell transplant. The data collected will assist in determining appropriate intervention and treatment plans for patients enrolled on this study. In addition, future patients may benefit by having the ability to anticipate problems and develop methods of prevention or early intervention.

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  • Natural History Study of SCID Disorders Recruiting

    This study is a prospective evaluation of children with Severe Combined Immune Deficiency (SCID) who are treated under a variety of protocols used by participating institutions. In order to determine the patient, recipient and transplant-related variables that are most important in determining outcome, study investigators will uniformly collect pre-, post- and peri-transplant (or other treatment) information on all children enrolled into this study. Children will be divided into three strata: - Stratum A: Typical SCID with virtual absence of autologous T cells and poor T cell function - Stratum B: Atypical SCID (leaky SCID, Omenn syndrome and reticular dysgenesis with limited T cell diversity or number and reduced function), and - Stratum C: ADA deficient SCID and XSCID patients receiving alternative therapy including PEG-ADA ERT or gene therapy. Each Group/Cohort Stratum will be analyzed separately.

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  • Observational Study to Evaluate Allogeneic HSCT Outcomes for Cerebral Adrenoleukodystrophy (CALD) Recruiting

    Study ALD-103 will be a multi-site, global, prospective and retrospective data collection study that is designed to evaluate outcomes of allo-HSCT in male subjects with CALD ≤17 years of age.

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  • Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995 Recruiting

    Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone marrow transplantation (BMT) has been shown to be curative. However the risks of transplantation are high and not all patients with CGD may need to undergo this high risk procedure. This study will determine the long term medical condition and daily functioning of participants with CGD after a transplant and if possible, compare these results to participants who do not undergo a transplant.

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  • Patients Treated for SCID (1968-Present) Recruiting

    Individuals with a past diagnosis of severe combined immune deficiency (including many cases of "leaky SCID", Omenn syndrome, and reticular dysgenesis) who have undergone blood and marrow transplant, gene therapy, or enzyme replacement in the past may be eligible for this study. The purpose of study is to look backwards at what has already been done in the. Over 800 patients with SCID are expected to be enrolled, making this one of the largest studies ever to describe outcomes for patients with SCID treated at many different hospitals around North America.

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  • Study Comparing Efficacy and Safety of Defibrotide vs Best Supportive Care in the Prevention of Hepatic Veno-Occlusive Disease in Adult and Pediatric Patients Not Recruiting

    This study is to compare the efficacy and safety of defibrotide prophylaxis in addition to best supportive care versus best supportive care alone in the prevention of hepatic veno- occlusive disease (VOD) in adult and pediatric patients undergoing hematopoietic stem cell transplant who are at high risk or very high risk of developing VOD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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2023-24 Courses


Graduate and Fellowship Programs


  • Pediatric Hem/Onc (Fellowship Program)

All Publications


  • Relevance of lymphocyte proliferation to PHA in severe combined immunodeficiency (SCID) and T cell lymphopenia. Clinical immunology (Orlando, Fla.) Abraham, R. S., Basu, A., Heimall, J. R., Dunn, E., Yip, A., Kapadia, M., Kapoor, N., Satter, L. F., Buckley, R., O'Reilly, R., Cuvelier, G. D., Chandra, S., Bednarski, J., Chaudhury, S., Moore, T. B., Haines, H., Dávila Saldaña, B. J., Chellapandian, D., Rayes, A., Chen, K., Caywood, E., Chandrakasan, S., Lugt, M. T., Ebens, C., Teira, P., Shereck, E., Miller, H., Aquino, V., Eissa, H., Yu, L. C., Gillio, A., Madden, L., Knutsen, A., Shah, A. J., DeSantes, K., Barnum, J., Broglie, L., Joshi, A., Kleiner, G., Dara, J., Prockop, S., Martinez, C., Mousallem, T., Oved, J., Burroughs, L., Marsh, R., Torgerson, T. R., Leiding, J. W., Pai, S. Y., Kohn, D. B., Pulsipher, M. A., Griffith, L. M., Notarangelo, L. D., Cowan, M. J., Puck, J., Dvorak, C. C., Haddad, E. 2024: 109942

    Abstract

    Severe combined immunodeficiency (SCID) is characterized by a severe deficiency in T cell numbers. We analyzed data collected (n = 307) for PHA-based T cell proliferation from the PIDTC SCID protocol 6901, using either a radioactive or flow cytometry method. In comparing the two groups, a smaller number of the patients tested by flow cytometry had <10% of the lower limit of normal proliferation as compared to the radioactive method (p = 0.02). Further, in patients with CD3+ T cell counts between 51 and 300 cells/μL, there was a higher proliferative response with the PHA flow assay compared to the 3H-T assay (p < 0.0001), suggesting that the method of analysis influences the resolution and interpretation of PHA results. Importantly, we observed many SCID patients with profound T cell lymphopenia having normal T cell proliferation when assessed by flow cytometry. We recommend this test be considered only as supportive in the diagnosis of typical SCID.

    View details for DOI 10.1016/j.clim.2024.109942

    View details for PubMedID 38367737

  • Diagnosis and management of pyruvate kinase deficiency: international expert guidelines. The Lancet. Haematology Al-Samkari, H., Shehata, N., Lang-Robertson, K., Bianchi, P., Glenthoj, A., Sheth, S., Neufeld, E. J., Rees, D. C., Chonat, S., Kuo, K. H., Rothman, J. A., Barcellini, W., van Beers, E. J., Pospisilova, D., Shah, A. J., van Wijk, R., Glader, B., Manu Pereira, M. D., Andres, O., Kalfa, T. A., Eber, S. W., Gallagher, P. G., Kwiatkowski, J. L., Galacteros, F., Lander, C., Watson, A., Elbard, R., Peereboom, D., Grace, R. F. 2024

    Abstract

    Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100000 to one in 300000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

    View details for DOI 10.1016/S2352-3026(23)00377-0

    View details for PubMedID 38330977

  • Exagamglogene Autotemcel for Severe Sickle Cell Disease Frangoul, H., Locatelli, F., Sharma, A., Bhatia, M., Mapara, M., Molinari, L., Wall, D., Liem, R. I., Telfer, P., Shah, A. J., Cavazzana, M., Corbacioglu, S., Rondelli, D., Meisel, R., Dedeken, L., Lobitz, S., de Montalembert, M., Steinberg, M. H., Walters, M. C., Bower, L., Imren, S., Simard, C., Xuan, F., Zhou, W., Morrow, P., Hobbs, W., Grupp, S. AMER SOC HEMATOLOGY. 2023
  • Exagamglogene Autotemcel for Transfusion-Dependent ß-Thalassemia Locatelli, F., Lang, P., Corbacioglu, S., Wall, D., Meisel, R., Li, A. M., de La Fuente, J., Shah, A. J., Carpenter, B., Kwiatkowski, J. L., Mapara, M., Liem, R. I., Cappellini, M., Algeri, M., Kattamis, A., Sheth, S., Grupp, S., Kohli, P., Shi, D., Ross, L., Bobruff, Y., Simard, C., Zhang, L., Morrow, P., Hobbs, W., Frangoul, H. AMER SOC HEMATOLOGY. 2023
  • LENTIVIRAL-MEDIATED GENE THERAPY FOR SEVERE PYRUVATE KINASE DEFICIENCY: RESULTS FROM AN ONGOING GLOBAL PHASE 1 STUDY Lopez Lorenzo, J., Shah, A., Sevilla, J., Navarro, S., Llanos, L., de Camino Gaisse, B., Sanchez, S., Zubicaray, J., Glader, B., Chien, M., Quintana Bustamante, O., Zeini, M., Choi, G., Nicoletti, E., Rao, G., Roncarolo, M., Bueren, J., Schwartz, J., Carlos Segovia, J. SPRINGERNATURE. 2023: 275-276
  • Busulfan and subsequent malignancy: An evidence-based risk assessment. Pediatric blood & cancer Long-Boyle, J. R., Kohn, D. B., Shah, A. J., Spencer, S. M., Sevilla, J., Booth, C., López Lorenzo, J. L., Nicoletti, E., Shah, A., Reatz, M., Matos, J., Schwartz, J. D. 2023: e30738

    Abstract

    The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted.We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3 years of follow-up.We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12 years.The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.

    View details for DOI 10.1002/pbc.30738

    View details for PubMedID 37856098

  • Post-Transplant Late Complications Increase Over Time for Patients with SCID: A Primary Immune Deficiency Treatment Consortium (PIDTC) Landmark Study. The Journal of allergy and clinical immunology Eissa, H., Thakar, M., Shah, A. J., Logan, B., Griffith, L. M., Dong, H., Parrott, R. E., O'Reilly, R., Dara, J., Kapoor, N., Satter, L. F., Chandra, S., Kapadia, M., Chandrakasan, S., Knutsen, A., Jyonouchi, S. C., Molinari, L., Rayes, A., Ebens, C. L., Teira, P., Dávila Saldaña, B. J., Burroughs, L. M., Chaudhury, S., Chellapandian, D., Gillio, A. P., Goldman, F., Malech, H. L., DeSantes, K., Cuvelier, G. D., Rozmus, J., Quinones, R., Yu, L. C., Broglie, L., Aquino, V., Shereck, E., Moore, T. B., Lugt, M. V., Mousallem, T. I., Oved, J. H., Dorsey, M., Azim, H. A., Martinez, C., Bleesing, J., Prockop, S., Kohn, D. B., Bednarski, J. J., Leiding, J., Marsh, R. A., Torgerson, T., Notarangelo, L. D., Pai, S. Y., Pulsipher, M. A., Puck, J. M., Dvorak, C. C., Haddad, E., Buckley, R. H., Cowan, M. J., Heimall, J. 2023

    Abstract

    To investigate outcomes of hematopoietic cell transplantation (HCT) for severe combined immunodeficiency (SCID), the Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children in the United States and Canada in a retrospective, multi-center natural history study.We evaluated the chronic and late effects (CLE) after HCT for SCID in 399 patients transplanted from 1982-2012 at 32 PIDTC centers. Eligibility criteria included survival to at least 2 years post-HCT without need for subsequent cellular therapy. CLE were defined as either conditions present at any time before 2 years from HCT that remained unresolved (chronic), or new conditions that developed beyond 2 years after HCT (late).The cumulative incidence of CLE was 25% in those alive at 2 years, increasing to 41% at 15 years after HCT. CLE were most prevalent in the neurologic (9%), neurodevelopmental (8%) and dental (8%) categories. Chemotherapy-based conditioning was associated with decreased height z-score at 2-5 years post-HCT (p<0.001), and endocrine (p<0.001) and dental (p=0.05) CLE. CD4 count ≤500/μl and/or continued need for immunoglobulin replacement >2 years post-transplant were associated with lower height z-scores. Continued survival from 2 to 15 years post-HCT was 90%. The presence of any CLE was associated with increased risk of late death (HR 7.21; 2.71-19.18, p<0.001).Late morbidity post-HCT for SCID was substantial, with an adverse impact on overall survival. This study provides evidence for development of survivorship guidelines based on disease characteristics and treatment exposures for patients after HCT for SCID.

    View details for DOI 10.1016/j.jaci.2023.09.027

    View details for PubMedID 37793572

  • Genotype, Oxidase Status, and Preceding Infection or Autoinflammation Do Not Affect Allogeneic HCT Outcomes for CGD. Blood Leiding, J. W., Arnold, D. E., Parikh, S. H., Logan, B. R., Marsh, R. A., Griffith, L. M., Wu, R., Kidd, S., Mallhi, K. K., Chellapandian, D., Si Lim, S., Grunebaum, E., Falcone, E. L., Murguia-Favela, L., Grossman, D., Prasad, V. K., Heimall, J. R., Touzot, F., Burroughs, L., Bleesing, J., Kapoor, N., Dara, J., Williams, O., Kapadia, M., Oshrine, B. R., Bednarski, J. J., Rayes, A., Chong, H., Cuvelier, G. D., Forbes Satter, L. R., Martinez, C., Vander Lugt, M. T., Yu, L. C., Chandrakasan, S., Joshi, A., Prockop, S. E., Davila Saldana, B. J., Aquino, V., Broglie, L., Ebens, C. L., Madden, L. M., DeSantes, K., Milner, J., Rangarajan, H. G., Shah, A., Gilio, A. P., Knutsen, A. P., Miller, H. K., Moore, T. B., Graham, P., Bauchat, A., Bunin, N. J., Teira, P., Petrovic, A., Chandra, S., Abdel-Azim, H., Dorsey, M., Birbrayer, O., Cowan, M. J., Dvorak, C. C., Haddad, E., Kohn, D. B., Notarangelo, L. D., Pai, S., Puck, J. M., Pulsipher, M. A., Torgerson, T. R., Malech, H. L., Kang, E. M. 2023

    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;n=151) enrolled from 2004-2018 or who underwent HCT (n=240) from 1996-2018. Median follow-up post-HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In multivariate analysis, Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively impacted survival. Age, genotype, and oxidase status did not impact outcomes. Pre-HCT, patients had higher infection density, higher frequency of non-infectious lung and liver disease, and more steroid use compared to conventionally-treated patients, yet 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 second HCT occurred in 17.6% and was associated with melphalan-based conditioning and/or early mixed chimerism. By 3-5 years post-HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of anti-microbial prophylaxis or corticosteroid use compared to both their baseline and to conventionally-treated patients. HCT leads to durable resolution of CGD symptoms and lowers burden of disease. Patients with active infection or inflammation are candidates for transplant; HCT should be considered prior to the development of co-morbidities that could impact performance status. Clinical trial # NCT02082353.

    View details for DOI 10.1182/blood.2022019586

    View details for PubMedID 37562003

  • Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. Lancet (London, England) Thakar, M. S., Logan, B. R., Puck, J. M., Dunn, E. A., Buckley, R. H., Cowan, M. J., O'Reilly, R. J., Kapoor, N., Satter, L. F., Pai, S., Heimall, J., Chandra, S., Ebens, C. L., Chellapandian, D., Williams, O., Burroughs, L. M., Saldana, B. D., Rayes, A., Madden, L. M., Chandrakasan, S., Bednarski, J. J., DeSantes, K. B., Cuvelier, G. D., Teira, P., Gillio, A. P., Eissa, H., Knutsen, A. P., Goldman, F. D., Aquino, V. M., Shereck, E. B., Moore, T. B., Caywood, E. H., Lugt, M. T., Rozmus, J., Broglie, L., Yu, L. C., Shah, A. J., Andolina, J. R., Liu, X., Parrott, R. E., Dara, J., Prockop, S., Martinez, C. A., Kapadia, M., Jyonouchi, S. C., Sullivan, K. E., Bleesing, J. J., Chaudhury, S., Petrovic, A., Keller, M. D., Quigg, T. C., Parikh, S., Shenoy, S., Seroogy, C., Rubin, T., Decaluwe, H., Routes, J. M., Torgerson, T. R., Leiding, J. W., Pulsipher, M. A., Kohn, D. B., Griffith, L. M., Haddad, E., Dvorak, C. C., Notarangelo, L. D. 2023

    Abstract

    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 chi2 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.

    View details for DOI 10.1016/S0140-6736(23)00731-6

    View details for PubMedID 37352885

  • Viral-specific T cells for Cytomegalovirus retinitis following hematopoietic stem cell transplantation: A success story. Pediatric blood & cancer Montiel-Esparza, R., Michalak, S. M., Le, A. H., Or, C., Nguyen, Q. D., Khoury, R., Grimley, M. S., Bertaina, A., Klinger, E., Shah, A. J., Wood, E. H. 2023: e30429

    Abstract

    Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

    View details for DOI 10.1002/pbc.30429

    View details for PubMedID 37243390

  • Global Phase 1 Study Results of Lentiviral Mediated Gene Therapy for Severe Pyruvate Kinase Deficiency Shah, A. J., Lopez Lorenzo, J., Sevilla, J., Navarro, S., Llanos, L., de Camino Gaisse, B., Sanchez, S., Zubicaray, J., Glader, B., Chien, M., Quintana Bustamante, O., Zeini, M., Choi, G., Nicoletti, E., Rao, G., Roncarolo, M., Bueren, J. A., Schwartz, J., Carlos Segovia, J. CELL PRESS. 2023: 118-119
  • Chronic granulomatous disease identified in the evaluation of atypical Kawasaki disease in an infant Solomon, B., Reddy, A., Konvinse, K., Shah, A., Gernez, Y., Mony, V. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: 133
  • The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions. The Journal of allergy and clinical immunology Dvorak, C. C., Haddad, E., Heimall, J., Dunn, E., Cowan, M. J., Pai, S., Kapoor, N., Satter, L. F., Buckley, R. H., O'Reilly, R. J., Chandra, S., Bednarski, J. J., Williams, O., Rayes, A., Moore, T. B., Ebens, C. L., Davila Saldana, B. J., Petrovic, A., Chellapandian, D., Cuvelier, G. D., Vander Lugt, M. T., Caywood, E. H., Chandrakasan, S., Eissa, H., Goldman, F. D., Shereck, E., Aquino, V. M., Desantes, K. B., Madden, L. M., Miller, H. K., Yu, L., Broglie, L., Gillio, A., Shah, A. J., Knutsen, A. P., Andolina, J. P., Joshi, A. Y., Szabolcs, P., Kapadia, M., Martinez, C. A., Parrot, R. E., Sullivan, K. E., Prockop, S. E., Abraham, R. S., Thakar, M. S., Leiding, J. W., Kohn, D. B., Pulsipher, M. A., Griffith, L. M., Notarangelo, L. D., Puck, J. M. 2022

    Abstract

    BACKGROUND: Shearer etal 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.

    View details for DOI 10.1016/j.jaci.2022.10.021

    View details for PubMedID 36456360

  • The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions. The Journal of allergy and clinical immunology Dvorak, C. C., Haddad, E., Heimall, J., Dunn, E., Buckley, R. H., Kohn, D. B., Cowan, M. J., Pai, S., Griffith, L. M., Cuvelier, G. D., Eissa, H., Shah, A. J., O'Reilly, R. J., Pulsipher, M. A., Wright, N. A., Abraham, R. S., Satter, L. F., Notarangelo, L. D., Puck, J. M. 2022

    Abstract

    Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 * 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells. Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers. These patients must also have either pathogenic variant(s) in a SCID-associated gene or reduced T-cell proliferation to certain mitogens. Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly. Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. Application of these revised Primary Immune Deficiency Treatment Consortium 2022 Definitions permits precise categorization of patients with T-cell defects but does not imply a preferred treatment strategy.

    View details for DOI 10.1016/j.jaci.2022.10.022

    View details for PubMedID 36456361

  • Lentiviral-mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study Shah, A. J., Lopez Lorenzo, J., Sevilla, J., Navarro, S., Llanos, L., de Camino Gaisse, B., Sanchez, S., Zubicaray, J., Glader, B., Chien, M., Bustamante, O., Zeini, M., Choi, G., Nicoletti, E., Rao, G. R., Grazia Roncarolo, M., Bueren, J. A., Schwartz, J. D., Segovia, J. C. AMER SOC HEMATOLOGY. 2022: 4902-4903
  • Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent beta-Thalassemia Locatelli, F., Lang, P., Li, A., Corbacioglu, S., de la Fuente, J., Wall, D. A., Liem, R., Meisel, R., Mapara, M. Y., Shah, A. J., Cappellini, M., Kattamis, A., Sheth, S., Bobruff, Y., Bower, L., Zhang, L., Sharma, A., Song, Y., Hobbs, W., Frangoul, H. AMER SOC HEMATOLOGY. 2022: 4899-4901
  • Mitapivat versus Placebo for Pyruvate Kinase Deficiency. The New England journal of medicine Shah, A. J., Schwartz, J. D., Segovia, J. C. 2022; 386 (26): 2538-2539

    View details for DOI 10.1056/NEJMc2206275

    View details for PubMedID 35767453

  • Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia. The New England journal of medicine Bertaina, A., Grimm, P. C., Weinberg, K., Parkman, R., Kristovich, K. M., Barbarito, G., Lippner, E., Dhamdhere, G., Ramachandran, V., Spatz, J. M., Fathallah-Shaykh, S., Atkinson, T. P., Al-Uzri, A., Aubert, G., van der Elst, K., Green, S. G., Agarwal, R., Slepicka, P. F., Shah, A. J., Roncarolo, M. G., Gallo, A., Concepcion, W., Lewis, D. B. 2022; 386 (24): 2295-2302

    Abstract

    Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of alphabeta T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).

    View details for DOI 10.1056/NEJMoa2117028

    View details for PubMedID 35704481

  • Outcomes Following Treatment for Adenosine Deaminase Deficient Severe Combined Immunodeficiency: A Report from the PIDTC. Blood Cuvelier, G. D., Logan, B. R., Prockop, S., Buckley, R. H., Kuo, C. Y., Griffith, L. M., Liu, X., Yip, A., Hershfield, M., Ayoub, P., Moore, T. B., Dorsey, M., O'Reilly, R. J., Kapoor, N., Pai, S. Y., Kapadia, M., Ebens, C. L., Forbes Satter, L. R., Burroughs, L., Petrovic, A., Chellapandian, D., Heimall, J., Shyr, D., Rayes, A., Bednarski, J. J., Chandra, S., Chandrakasan, S., Gilio, A. P., Madden, L. M., Quigg, T. C., Caywood, E. H., Dávila Saldaña, B. J., DeSantes, K., Eissa, H., Goldman, F. D., Rozmus, J., Shah, A., Vander Lugt, M. T., Thakar, M. S., Parrott, R. E., Martinez, C. A., Leiding, J. W., Torgerson, T. R., Pulsipher, M. A., Notarangelo, L. D., Cowan, M. J., Dvorak, C. C., Haddad, E., Puck, J. M., Kohn, D. B. 2022

    Abstract

    Adenosine deaminase (ADA) deficiency causes ~13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 ADA-SCID patients diagnosed between 1982-2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies. Baseline clinical, immunologic, genetic characteristics and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT) (p<0.01). Overall survival (OS) at 5-years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT) (p=0.01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs. 68% if ≥3.5 months, p=0.02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs. 68.2%, p<0.01) and OS (64.7% vs. 82.3%, p=0.02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies ADA-SCID patients soon after birth and before the onset of infections.

    View details for DOI 10.1182/blood.2022016196

    View details for PubMedID 35671392

  • Male-Specific Late Effects in Adult Hematopoietic Cell Transplantation Recipients: A Systematic Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation TRANSPLANTATION AND CELLULAR THERAPY Phelan, R., Im, A., Hunter, R. L., Inamoto, Y., Lupo-Stanghellini, M., Rovo, A., Badawy, S. M., Burns, L., Eissa, H., Murthy, H. S., Prasad, P., Sharma, A., Suelzer, E., Agrawal, V., Aljurf, M., Baker, K., Basak, G. W., Buchbinder, D., DeFilipp, Z., Grkovic, L., Dias, A., Einsele, H., Eisenberg, M. L., Epperla, N., Farhadfar, N., Flatau, A., Gale, R., Greinix, H., Hamilton, B. K., Hashmi, S., Hematti, P., Jamani, K., Maharaj, D., Murray, J., Naik, S., Nathan, S., Pavletic, S., Peric, Z., Pulanic, D., Ross, R., Salonia, A., Sanchez-Ortega, I., Savani, B. N., Schechter, T., Shah, A. J., Smith, S. M., Snowden, J. A., Steinberg, A., Tremblay, D., Vij, S. C., Walker, L., Wolff, D., Yared, J. A., Schoemans, H., Tichelli, A. 2022; 28 (6)
  • Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Bone marrow transplantation Phelan, R., Im, A., Hunter, R. L., Inamoto, Y., Lupo-Stanghellini, M. T., Rovo, A., Badawy, S. M., Burns, L., Eissa, H., Murthy, H. S., Prasad, P., Sharma, A., Suelzer, E., Agrawal, V., Aljurf, M., Baker, K., Basak, G. W., Buchbinder, D., DeFilipp, Z., Grkovic, L. D., Dias, A., Einsele, H., Eisenberg, M. L., Epperla, N., Farhadfar, N., Flatau, A., Gale, R. P., Greinix, H., Hamilton, B. K., Hashmi, S., Hematti, P., Jamani, K., Maharaj, D., Murray, J., Naik, S., Nathan, S., Pavletic, S., Peric, Z., Pulanic, D., Ross, R., Salonia, A., Sanchez-Ortega, I., Savani, B. N., Schechter, T., Shah, A. J., Smith, S. M., Snowden, J. A., Steinberg, A., Tremblay, D., Vij, S. C., Walker, L., Wolff, D., Yared, J. A., Schoemans, H., Tichelli, A. 2022

    Abstract

    Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research.

    View details for DOI 10.1038/s41409-022-01591-z

    View details for PubMedID 35523848

  • Stemming the Tide of Gastrointestinal Chronic Granulomatous Disease. Digestive diseases and sciences Cagil, Y., Tong, E., Guimaraes, C., Andrews, J., Abu El Haija, M., Triadafilopoulos, G., Yeh, A. M., Shah, A. 2022

    View details for DOI 10.1007/s10620-022-07492-x

    View details for PubMedID 35397696

  • Transplanted CGD Patients have Higher Burden of Disease than Conventionally Treated Patients that Resolve with Transplantation - A PIDTC Report Leiding, J., Danielle, A., Parikh, S., Logan, B., Marsh, R., Griffith, L., Wu, R., Mallhi, K., Chellapandian, D., Lim, S., Grunebaum, E., Broglie, L., Prasad, V., Heimall, J., Bunin, N., Teira, P., Touzot, F., Burroughs, L., Petrovic, A., Bleesing, J., Chandra, S., Kapoor, N., Dara, J., Dorsey, M., Williams, O., Kapadia, M., Bednarski, J., Rayes, A., Chen, K., Chong, H., Cuvelier, G., Forbes-Satter, L., Martinez, C., Lugt, M., Yu, L., Chandrakasan, S., Joshi, A., Prockop, S., Saldana, B., Aquino, V., Ebens, C., Madden, L., DeSantes, K., Milner, J., Rangarajan, H., Shah, A., Gillio, A., Knutsen, A., Miller, H., Moore, T., Favela, L., Cowan, M. J., Dvorak, C. C., Haddad, E., Kohn, D. B., Notarangelo, L. D., Pai, S., Puck, J. M., Pulsipher, M. A., Torgerson, T., Malech, H. L., Kang, E. M. SPRINGER/PLENUM PUBLISHERS. 2022: S76-S78
  • Sequential hematopoietic stem cell transplantation (HSCT) followed by kidney transplant-3 children who received ABT-cell/CD19 B-cell depleted HSCT followed by kidney transplant from same parental donor are rejection free and immunosuppression free with donor specific tolerance > 1year post kidney transplant Grimm, P., Lewis, D. B., Al-Uzri, A., Fathallah-Shaykh, S., Shah, A., Agarwal, R., Weinberg, K. I., Gallo, A., Concepcion, W., Bertaina, A. WILEY. 2022
  • Who Should be Eligible for Gene Therapy Clinical Trials in Red Blood Cell Pyruvate Kinase Deficiency (PKD)?: Towards an Expanded Definition of Severe PKD. American journal of hematology Schwartz, J. D., Barcellini, W., Grace, R. F., Bianchi, P., Zanella, A., Lopez Lorenzo, J. L., Sevilla, J., Shah, A. J., Glader, B., Nicoletti, E., Ordonez, S. N., Segovia, J. C. 1800

    View details for DOI 10.1002/ajh.26458

    View details for PubMedID 34989415

  • Functional Immune Tolerance Induced By Sequential Hematopoietic Stem Cell-Solid Organ Transplantation Bertaina, A., Barbarito, G., Ramachandran, V. V., Kristovich, K., Lippner, E., Fathallah-Shaykh, S., Al-Uzri, A., Shah, A. J., Aubert, G., Slepicka, P., Oppizzi, L., Agarwal, R., Roncarolo, M., Gallo, A., Concepcion, W., Weinberg, K. I., Parkman, R., Lewis, D. B., Grimm, P. C. AMER SOC HEMATOLOGY. 2021: 1818-+
  • Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: Interim Results of a Global Phase 1 Study for Adult and Pediatric Patients Shah, A. J., Lopez Lorenzo, J., Navarro, S., Sevilla, J., Llanos, L., Perez de Camino Gaisse, B., Sanchez, S., Glader, B., Chien, M., Quintana Bustamante, O., Beard, B. C., Law, K. M., Zeini, M., Choi, G., Nicoletti, E., Rao, G. R., Grazia Roncarolo, M., Bueren, J. A., Schwartz, J. D., Segovia, J. C. AMER SOC HEMATOLOGY. 2021
  • Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. The New England journal of medicine Kohn, D. B., Booth, C., Shaw, K. L., Xu-Bayford, J., Garabedian, E., Trevisan, V., Carbonaro-Sarracino, D. A., Soni, K., Terrazas, D., Snell, K., Ikeda, A., Leon-Rico, D., Moore, T. B., Buckland, K. F., Shah, A. J., Gilmour, K. C., De Oliveira, S., Rivat, C., Crooks, G. M., Izotova, N., Tse, J., Adams, S., Shupien, S., Ricketts, H., Davila, A., Uzowuru, C., Icreverzi, A., Barman, P., Campo Fernandez, B., Hollis, R. P., Coronel, M., Yu, A., Chun, K. M., Casas, C. E., Zhang, R., Arduini, S., Lynn, F., Kudari, M., Spezzi, A., Zahn, M., Heimke, R., Labik, I., Parrott, R., Buckley, R. H., Reeves, L., Cornetta, K., Sokolic, R., Hershfield, M., Schmidt, M., Candotti, F., Malech, H. L., Thrasher, A. J., Gaspar, H. B. 2021

    Abstract

    BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up.RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).

    View details for DOI 10.1056/NEJMoa2027675

    View details for PubMedID 33974366

  • Lentiviral Mediated Gene Therapy for Pyruvate Kinase Deficiency: Updated Results of a Global Phase 1 Study for Adult and Pediatric Patients Lopez Lorenzo, J., Shah, A. J., Navarro, S., Sevilla, J., Llanos, L., Perez Camino de Gaisse, B., Sanchez, S., Glader, B., Chien, M., Quintana-Bustamante, O., Beard, B. C., Law, K. M., Zeini, M., Choi, G., Nicoletti, E., Rao, G. R., Roncarolo, M., Bueren, J. A., Schwartz, J. D., Segovia, J. C. CELL PRESS. 2021: 42-43
  • Return to Work Among Young Adult Survivors of Allogeneic Hematopoietic Cell Transplantation in the United States. Transplantation and cellular therapy Bhatt, N. S., Brazauskas, R., Salit, R. B., Syrjala, K., Bo-Subait, S., Tecca, H., Badawy, S. M., Baker, K. S., Beitinjaneh, A., Bejanyan, N., Byrne, M., Dias, A., Farhadfar, N., Freytes, C. O., Ganguly, S., Hashmi, S., Hayashi, R. J., Hong, S., Inamoto, Y., Jamani, K., Kasow, K. A., Khera, N., Krem, M. M., Lazarus, H. M., Lee, C. J., Lee, S., Majhail, N. S., Malone, A. K., Marks, D. I., Mau, L., Mayo, S. J., Muffly, L. S., Nathan, S., Nishihori, T., Page, K. M., Preussler, J., Rangarajan, H. G., Rotz, S. J., Salooja, N., Savani, B. N., Schears, R., Schechter-Finkelstein, T., Schiller, G., Shah, A. J., Sharma, A., Wang, T., Wirk, B., Battiwalla, M., Schoemans, H., Hamilton, B., Buchbinder, D., Phelan, R., Shaw, B. 2021

    Abstract

    BACKGROUND: Young adult (YA) survivors of allogeneic hematopoietic cell transplant (HCT) are at risk for late psychosocial challenges, including inability to return to work post-HCT. However, work-related outcomes in this population remain understudied.OBJECTIVES: To assess the post-HCT work status of survivors of allogeneic HCT who underwent HCT as YA and analyze the patient-, disease-, and HCT-related factors associated with their work status at 1-year post-HCT.STUDY DESIGN: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we described post-HCT work status (full-time, part-time work, unemployed, and medical disability) of YA HCT survivors (N=1365) who underwent HCT between 2008 and 2015. Percentages of work status categories were reported at four timepoints: 6-months, 1-, 2-, and 3-year post-HCT. Percentages of post-HCT work status categories at the 1-year timepoint were also described in relation to survivors' pre-HCT work status categories. Factors associated with 1-year post-HCT work status (full-time or part-time work) were examined using logistic regression.RESULTS: From 6 months to 3 years post-HCT, the percentage of survivors working full-time and part-time increased from 18.3% to 50.7%, and from 6.9% to 10.5%, respectively. Of patients in full-time work pre-HCT, 50% were unemployed or on medical disability at 1-year post-HCT. Female sex (Odds ratio [OR] 0.55; 95% confidence interval [CI] 0.40-0.77), HCT-comorbidity index (HCT-CI) score ≥3 (OR 0.57; 95% CI 0.39-0.82), pre-HCT unemployment (OR 0.37; 95% CI 0.24-0.56), and medical disability (OR 0.44; 95% CI 0.28-0.70), development of grade 3-4 acute graft vs. host disease (OR 0.52; 95% CI 0.34-0.80), and relapse within one-year post-HCT (OR 0.34; 95% CI 0.21-0.56) were associated with lower likelihood of employment at 1-year post-HCT. Compared to myeloablative conditioning with total body irradiation (TBI), myeloablative conditioning without TBI (OR 1.71; 95% CI 1.16-2.53) was associated with higher likelihood of employment at 1-year post-HCT. Graduate school level education (OR 2.47; 95% CI 1.49-4.10) was also associated with higher likelihood of employment at 1-year post-HCT.CONCLUSIONS: While the work status among YA HCT survivors continued to improve over time, a substantial subset became or remained unemployed or on medical disability. These findings underscore the need for effective return to work supportive interventions in this population.

    View details for DOI 10.1016/j.jtct.2021.04.013

    View details for PubMedID 33895402

  • Immune function in childhood cancer survivors: a Children's Oncology Group review. The Lancet. Child & adolescent health Guilcher, G. M., Rivard, L., Huang, J. T., Wright, N. A., Anderson, L., Eissa, H., Pelletier, W., Ramachandran, S., Schechter, T., Shah, A. J., Wong, K., Chow, E. J. 2021

    Abstract

    Childhood cancer and its treatment often impact the haematopoietic and lymphatic systems, with immunological consequences. Immunological assessments are not routinely included in surveillance guidelines for most survivors of childhood cancer, although a robust body of literature describes immunological outcomes, testing recommendations, and revaccination guidelines after allogeneic haematopoietic cell transplantation. Survivorship care providers might not fully consider the impaired recovery of a child's immune system after cancer treatment if the child has not undergone haematopoietic cell transplantation. We did a scoping review to collate the existing literature describing immune function after childhood cancer therapy, including both standard-dose chemotherapy and high-dose chemotherapy with haematopoietic cell rescue. This Review aims to summarise: the principles of immunology and testing of immune function; the body of literature describing immunological outcomes after childhood cancer therapy, with an emphasis on the risk of infection, when is testing indicated, and preventive strategies; and knowledge gaps and opportunities for future research.

    View details for DOI 10.1016/S2352-4642(20)30312-6

    View details for PubMedID 33600774

  • Male-specific late effects in adult hematopoietic cell transplantation recipients: a systematic review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Transplantation and cellular therapy Phelan, R., Im, A., Hunter, R. L., Inamoto, Y., Lupo-Stanghellini, M. T., Rovo, A., Badawy, S. M., Burns, L., Eissa, H., Murthy, H. S., Prasad, P., Sharma, A., Suelzer, E., Agrawal, V., Aljurf, M., Baker, K., Basak, G. W., Buchbinder, D., DeFilipp, Z., Grkovic, L. D., Dias, A., Einsele, H., Eisenberg, M. L., Epperla, N., Farhadfar, N., Flatau, A., Gale, R. P., Greinix, H., Hamilton, B. K., Hashmi, S., Hematti, P., Jamani, K., Maharaj, D., Murray, J., Naik, S., Nathan, S., Pavletic, S., Peric, Z., Pulanic, D., Ross, R., Salonia, A., Sanchez-Ortega, I., Savani, B. N., Schechter, T., Shah, A. J., Smith, S. M., Snowden, J. A., Steinberg, A., Tremblay, D., Vij, S. C., Walker, L., Wolff, D., Yared, J. A., Schoemans, H., Tichelli, A. 2021

    Abstract

    Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT.Here, we provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.We utilized systematic review methodology to summarize incidence, risk factors, screening, prevention and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research.Most of the evidence regarding male GvHD is still based on limited data, precluding strong therapeutic recommendations. We therefore recommend to systematically screen for male genital GvHD regularly and report it to large registries to allow for a better understanding. Future research should also address treatment since little published evidence is available to date. Male-specific endocrine consequences of HCT include hypogonadism which may also affect bone health. Since the evidence is scarce, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, which warrants offering sperm preservation in all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, hence the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent than in the general population; however, subsequent malignancies in general seem to be more prevalent in males than females, and special attention should be given to skin and oral mucosa.Male-specific late effects, probably more under-reported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplant physicians and specialists from other involved disciplines. Future research should be directed towards better data collection on male-specific late effects and on studies about the interrelationship between these late effects, to allow the development of evidence based effective management practices.

    View details for DOI 10.1016/j.jtct.2021.10.013

    View details for PubMedID 34757220

  • Correction to: Infections in Infants with SCID: Isolation, Infection Screening and Prophylaxis in PIDTC Centers. Journal of clinical immunology Dorsey, M., Wright, N. A., Chaimowitz, N. S., Davila Saldana, B. J., Miller, H., Keller, M. D., Thakar, M. S., Shah, A. J., Abu-Arja, R., Andolina, J., Aquino, V., Barnum, J. L., Bednarski, J. J., Bhatia, M., Bonilla, F. A., Butte, M. J., Bunin, N. J., Burroughs, L. M., Chandra, S., Chaudhury, S., Chen, K., Chong, H., Cuvelier, G., Dalal, J., DeFelice, M. L., DeSantes, K. B., Forbes, L. R., Gillio, A., Goldman, F., Joshi, A. Y., Kapoor, N., Knutsen, A. P., Kobrynski, L., Lieberman, J. A., Leiding, J. W., Oshrine, B., Patel, K. P., Prockop, S., Quigg, T. C., Quinones, R., Schultz, K. R., Seroogy, C., Shyr, D., Siegel, S., Smith, A. R., Torgerson, T. R., Vander Lugt, M. T., Yu, L. C., Cowan, M. J., Buckley, R. H., Dvorak, C. C., Griffith, L. M., Haddad, E., Kohn, D. B., Logan, B., Notarangelo, L. D., Pai, S., Puck, J., Pulsipher, M. A., Heimall, J. 2020

    Abstract

    A Correction to this paper has been published: https://doi.org/10.1007/s10875-020-00917-0.

    View details for DOI 10.1007/s10875-020-00917-0

    View details for PubMedID 33274413

  • Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers. Journal of clinical immunology Dorsey, M. J., Wright, N. A., Chaimowitz, N. S., Davila Saldana, B. J., Miller, H., Keller, M. D., Thakar, M. S., Shah, A. J., Abu-Arja, R., Andolina, J., Aquino, V., Barnum, J. L., Bednarski, J. J., Bhatia, M., Bonilla, F. A., Butte, M. J., Bunin, N. J., Chandra, S., Chaudhury, S., Chen, K., Chong, H., Cuvelier, G. D., Dalal, J., DeFelice, M. L., DeSantes, K. B., Forbes, L. R., Gillio, A., Goldman, F., Joshi, A. Y., Kapoor, N., Knutsen, A. P., Kobrynski, L., Lieberman, J. A., Leiding, J. W., Oshrine, B., Patel, K. P., Prockop, S., Quigg, T. C., Quinones, R., Schultz, K. R., Seroogy, C., Shyr, D., Siegel, S., Smith, A. R., Torgerson, T. R., Vander Lugt, M. T., Yu, L. C., Cowan, M. J., Buckley, R. H., Dvorak, C. C., Griffith, L. M., Haddad, E., Kohn, D. B., Logan, B., Notarangelo, L. D., Pai, S., Puck, J., Pulsipher, M. A., Heimall, J. 2020

    Abstract

    PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention.METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management.RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p=0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p=0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented.CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS.TRIAL REGISTRATION: NCT01186913.

    View details for DOI 10.1007/s10875-020-00865-9

    View details for PubMedID 33006109

  • Correction: Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. Journal of clinical immunology Marsh, R. A., Leiding, J. W., Logan, B. R., Griffith, L. M., Arnold, D. E., Haddad, E., Falcone, E. L., Yin, Z., Patel, K., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L. M., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. D., Thakar, M. S., Chen, K., Teira, P., Shenoy, S., Phelan, R., Forbes, L. R., Martinez, C., Chellapandian, D., Davila Saldana, B. J., Shah, A. J., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Grossman, D., Torgerson, T., Graham, P., Prasad, V., Knutsen, A., Chong, H., Miller, H., de la Morena, M. T., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Stenger, E., Pai, S., Routes, J. M., Puck, J. M., Kapoor, N., Pulsipher, M. A., Malech, H. L., Parikh, S., Kang, E. M., submitted on behalf of the Primary Immune Deficiency Treatment Consortium 2020

    Abstract

    The original version of this article unfortunately contained the missing author, Caridad Martinez. The authors would like to correct the list. We apologize for any inconvenience that this may have caused. The correct author list is shown above.

    View details for DOI 10.1007/s10875-020-00852-0

    View details for PubMedID 32860171

  • CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells. Science advances Goodwin, M., Lee, E., Lakshmanan, U., Shipp, S., Froessl, L., Barzaghi, F., Passerini, L., Narula, M., Sheikali, A., Lee, C. M., Bao, G., Bauer, C. S., Miller, H. K., Garcia-Lloret, M., Butte, M. J., Bertaina, A., Shah, A., Pavel-Dinu, M., Hendel, A., Porteus, M., Roncarolo, M. G., Bacchetta, R. 2020; 6 (19): eaaz0571

    Abstract

    The prototypical genetic autoimmune disease is immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a severe pediatric disease with limited treatment options. IPEX syndrome is caused by mutations in the forkhead box protein 3 (FOXP3) gene, which plays a critical role in immune regulation. As a monogenic disease, IPEX is an ideal candidate for a therapeutic approach in which autologous hematopoietic stem and progenitor (HSPC) cells or T cells are gene edited ex vivo and reinfused. Here, we describe a CRISPR-based gene correction permitting regulated expression of FOXP3 protein. We demonstrate that gene editing preserves HSPC differentiation potential, and that edited regulatory and effector T cells maintain their in vitro phenotype and function. Additionally, we show that this strategy is suitable for IPEX patient cells with diverse mutations. These results demonstrate the feasibility of gene correction, which will be instrumental for the development of therapeutic approaches for other genetic autoimmune diseases.

    View details for DOI 10.1126/sciadv.aaz0571

    View details for PubMedID 32494707

    View details for PubMedCentralID PMC7202871

  • Excellent Outcomes Following Hematopoietic Cell Transplantation for Wiskott-Aldrich Syndrome: A PIDTC Report. Blood Burroughs, L., Petrovic, A., Brazauskas, R., Liu, X., Griffith, L. M., Ochs, H. D., Bleesing, J., Edwards, S., Dvorak, C. C., Chaudhury, S., Prockop, S., Quinones, R., Goldman, F., Quigg, T., Chandrakasan, S., Smith, A. R., Parikh, S. H., Davila Saldana, B. J., Thakar, M. S., Phelan, R., Shenoy, S., Forbes, L. R., Martinez, C. A., Chellapandian, D., Shereck, E., Miller, H., Kapoor, N., Barnum, J. L., Chong, H., Shyr, D., Chen, K., Abu-Arja, R. F., Shah, A., Weinacht, K., Moore, T. B., Joshi, A., DeSantes, K., Gillio, A. P., Cuvelier, G. D., Keller, M. D., Rozmus, J., Torgerson, T. R., Pulsipher, M. A., Haddad, E., Sullivan, K., Logan, B. R., Kohn, D. B., Puck, J. M., Notarangelo, L. D., Pai, S., Rawlings, D., Cowan, M. J. 2020

    Abstract

    Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. Here we report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers between 2005 and 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs. ≥5 years old at the time of HCT (94% vs. 66%, overall p=0.0008). OS was excellent regardless of donor type even in cord blood recipients (90%). Conditioning intensity did not impact OS, but was associated with donor T-cell and myeloid engraftment post-HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early post-HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) versus low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005 compared to prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution following either myeloablative or busulfan-containing reduced intensity conditioning. (www.clinicaltrials.gov NCT02064933.).

    View details for DOI 10.1182/blood.2019002939

    View details for PubMedID 32268350

  • Novel nonsense IKBKG Mutation in an Infant Presenting with Pneumocysti s Jiroveci Pneumonia and Disseminated Mycobacterium Szulgai Infection Lo, R., Rosenthal, A., Shah, A., Chen, S., Eguiguren, L., Siddiqi, A., Hernandez, J., Lewis, D. SPRINGER/PLENUM PUBLISHERS. 2020: S119–S120
  • A beta T-Cell/CD19 B-Cell Depleted Haploidentical Stem Cell Transplantation: A New Platform for Curing Rare and Monogenic Disorders Bertaina, A., Bacchetta, R., Lewis, D. B., Grimm, P. C., Shah, A. J., Agarwal, R., Concepcion, W., Czechowicz, A., Bhatia, N., Lahiri, P., Weinberg, K. I., Parkman, R., Porteus, M., Roncarolo, M. ELSEVIER SCIENCE INC. 2020: S288
  • Transplantation Outcomes for Children with Severe Combined Immune Deficiency (SCID) Have Improved over Time: A 36-Year Summary Report By the Primary Immune Deficiency Treatment Consortium (PIDTC) Thakar, M. S., Logan, B., Buckley, R. H., Haddad, E., Dvorak, C. C., O'Reilly, R. J., Kapoor, N., Satter, L., Martinez, C., Pai, S., Heimall, J., Jyonouchi, S., Sullivan, K. E., Chandra, S., Smith, A. R., Chaudhury, S., Saldana, B., Sunkersett, G., Shyr, D. C., Burroughs, L. M., Petrovic, A., Quigg, T. C., Shenoy, S., Bednarski, J. J., DeSantes, K., Cuvelier, G. E., Chandrakasan, S., Gillio, A. P., Knutsen, A. P., Eissa, H., Goldman, F., Moore, T. B., Aquino, V., Shereck, E., Lugt, M., Caywood, E. H., Yu, L. C., Rozmus, J., Talano, J. M., Malech, H. L., Shah, A. J., Abu-Arja, R., Miller, H. K., Bani-Hashemi, T., Chang, C. K., Dunn, E., Torgerson, T., Pulsipher, M. A., Griffith, L. M., Cowan, M. J., Kohn, D. B., Puck, J., Notarangelo, L. D. ELSEVIER SCIENCE INC. 2020: S18–S19
  • Experience with Ruxolitinib (Jakafi (R)) As a Salvage Therapy for Graft-Versus-Host Disease in Children and Young Adults Mavers, M., Klinger, E., Shyr, D. C., Shah, A. J., Bertaina, A., Soni, S. ELSEVIER SCIENCE INC. 2020: S179
  • Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation. Journal of clinical immunology Shah, A. J., Sokolic, R., Logan, B., Yin, Z., Iyengar, S., Scalchunes, C., Mangurian, C., Albert, M., Cowan, M. J. 2019

    Abstract

    BACKGROUND: We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families.MATERIALS AND METHODS: We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports.RESULTS: Sixty-eight patients (29 patients completed both the PedsQL 4.0 and the parent proxy form; 21 completed only the PedsQL 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p=0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p=<0.001), emotional functioning (69.91 vs. 82.64, p=<0.001), social functioning (77.55 vs. 91.56, p=<0.001), and school functioning (70.46 vs. 85.67, p=<0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry.CONCLUSION: These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.

    View details for DOI 10.1007/s10875-019-00689-2

    View details for PubMedID 31620947

  • Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. Journal of clinical immunology Marsh, R. A., Leiding, J. W., Logan, B. R., Griffith, L. M., Arnold, D. E., Haddad, E., Falcone, E. L., Yin, Z., Patel, K., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L. M., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. D., Thakar, M. S., Chen, K., Teira, P., Shenoy, S., Phelan, R., Forbes, L. R., Chellapandian, D., Davila Saldana, B. J., Shah, A. J., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Grossman, D., Torgerson, T., Graham, P., Prasad, V., Knutsen, A., Chong, H., Miller, H., de la Morena, M. T., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Stenger, E., Pai, S., Routes, J. M., Puck, J. M., Kapoor, N., Pulsipher, M. A., Malech, H. L., Parikh, S., Kang, E. M., submitted on behalf of the Primary Immune Deficiency Treatment Consortium 2019

    Abstract

    INTRODUCTION: Inflammatory 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.METHODS: We 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.RESULTS: Forty-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.CONCLUSIONS: In 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.

    View details for DOI 10.1007/s10875-019-00659-8

    View details for PubMedID 31376032

  • GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia. Blood advances Mehta, R. S., Holtan, S. G., Wang, T., Hemmer, M. T., Spellman, S. R., Arora, M., Couriel, D. R., Alousi, A. M., Pidala, J., Abdel-Azim, H., Ahmed, I., Aljurf, M., Askar, M., Auletta, J. J., Bhatt, V., Bredeson, C., Chhabra, S., Gadalla, S., Gajewski, J., Gale, R. P., Gergis, U., Hematti, P., Hildebrandt, G. C., Inamoto, Y., Kitko, C., Khandelwal, P., MacMillan, M. L., Majhail, N., Marks, D. I., Mehta, P., Nishihori, T., Olsson, R. F., Pawarode, A., Diaz, M. A., Prestidge, T., Qayed, M., Rangarajan, H., Ringden, O., Saad, A., Savani, B. N., Seo, S., Shah, A., Shah, N., Schultz, K. R., Solh, M., Spitzer, T., Szer, J., Teshima, T., Verdonck, L. F., Williams, K. M., Wirk, B., Wagner, J., Yared, J. A., Weisdorf, D. J. 2019; 3 (9): 1441–49

    Abstract

    We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P < .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P < .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

    View details for PubMedID 31053571

  • GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia BLOOD ADVANCES Mehta, R. S., Holtan, S. G., Wang, T., Hemmer, M. T., Spellman, S. R., Arora, M., Couriel, D. R., Alousi, A. M., Pidala, J., Abdel-Azim, H., Ahmed, I., Aljurf, M., Askar, M., Auletta, J. J., Bhatt, V., Bredeson, C., Chhabra, S., Gadalla, S., Gajewski, J., Gale, R., Gergis, U., Hematti, P., Hildebrandt, G. C., Inamoto, Y., Kitko, C., Khandelwal, P., MacMillan, M. L., Majhail, N., Marks, D., Mehta, P., Nishihori, T., Olsson, R. F., Pawarode, A., Diaz, M., Prestidge, T., Qayed, M., Rangarajan, H., Ringden, O., Saad, A., Savani, B. N., Seo, S., Shah, A., Shah, N., Schultz, K. R., Solh, M., Spitzer, T., Szer, J., Teshima, T., Verdonck, L. F., Williams, K. M., Wirk, B., Wagner, J., Yared, J. A., Weisdorf, D. J. 2019; 3 (9): 1441–49
  • Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Inamoto, Y., Petricek, I., Burns, L., Chhabra, S., DeFilipp, Z., Hematti, P., Rovo, A., Schears, R., Shah, A., Agrawal, V., Ahmed, A., Ahmed, I., Ali, A., Aljurf, M., Alkhateeb, H., Beitinjaneh, A., Bhatt, N., Buchbinder, D., Byrne, M., Callander, N., Fahnehjelm, K., Farhadfar, N., Gale, R., Ganguly, S., Hashmi, S., Hildebrandt, G. C., Horn, E., Jakubowski, A., Kamble, R. T., Law, J., Lee, C., Nathan, S., Penack, O., Pingali, R., Prasad, P., Pulanic, D., Rotz, S., Shreenivas, A., Steinberg, A., Tabbara, K., Tichelli, A., Wirk, B., Yared, J., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. D., Shaw, B. E., Valdes-Sanz, N. 2019; 25 (5): E145–E154
  • Correction: Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. Bone marrow transplantation Inamoto, Y., Petricek, I., Burns, L., Chhabra, S., DeFilipp, Z., Hematti, P., Rovo, A., Schears, R., Shah, A., Agrawal, V., Al-Khinji, A., Ahmed, I., Ali, A., Aljurf, M., Alkhateeb, H., Beitinjaneh, A., Bhatt, N., Buchbinder, D., Byrne, M., Callander, N., Fahnehjelm, K., Farhadfar, N., Gale, R. P., Ganguly, S., Hildebrandt, G. C., Horn, E., Jakubowski, A., Kamble, R. T., Law, J., Lee, C., Nathan, S., Penack, O., Pingali, R., Prasad, P., Pulanic, D., Rotz, S., Shreenivas, A., Steinberg, A., Tabbara, K., Tichelli, A., Wirk, B., Yared, J., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. E., Shaw, B. E., Valdes-Sanz, N. 2019

    Abstract

    In the original version of this article, author 'Aisha Al-Khinji' was incorrectly listed as 'Aisha Ahmed'. This has now been corrected in both the PDF and HTML versions of the article to 'Aisha Al-Khinji'.

    View details for DOI 10.1038/s41409-019-0472-x

    View details for PubMedID 30809032

  • Non-GVHD ocular complications after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. Bone marrow transplantation Inamoto, Y., Petricek, I., Burns, L., Chhabra, S., DeFilipp, Z., Hematti, P., Rovo, A., Schears, R., Shah, A., Agrawal, V., Ahmed, A., Ahmed, I., Ali, A., Aljurf, M., Alkhateeb, H., Beitinjaneh, A., Bhatt, N., Buchbinder, D., Byrne, M., Callander, N., Fahnehjelm, K., Farhadfar, N., Gale, R. P., Ganguly, S., Hildebrandt, G. C., Horn, E., Jakubowski, A., Kamble, R. T., Law, J., Lee, C., Nathan, S., Penack, O., Pingali, R., Prasad, P., Pulanic, D., Rotz, S., Shreenivas, A., Steinberg, A., Tabbara, K., Tichelli, A., Wirk, B., Yared, J., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. E., Shaw, B. E., Valdes-Sanz, N. 2018

    Abstract

    Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.

    View details for DOI 10.1038/s41409-018-0339-6

    View details for PubMedID 30531955

  • Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. Bone marrow transplantation Inamoto, Y., Valdes-Sanz, N., Ogawa, Y., Alves, M., Berchicci, L., Galvin, J., Greinix, H., Hale, G. A., Horn, B., Kelly, D., Liu, H., Rowley, S., Schoemans, H., Shah, A., Lupo Stanghellini, M. T., Agrawal, V., Ahmed, I., Ali, A., Bhatt, N., Byrne, M., Chhabra, S., DeFilipp, Z., Fahnehjelm, K., Farhadfar, N., Horn, E., Lee, C., Nathan, S., Penack, O., Prasad, P., Rotz, S., Rovo, A., Yared, J., Pavletic, S., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. E., Shaw, B. E., Petricek, I. 2018

    Abstract

    Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

    View details for DOI 10.1038/s41409-018-0340-0

    View details for PubMedID 30531954

  • Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Inamoto, Y., Petricek, I., Burns, L., Chhabra, S., DeFilipp, Z., Hematti, P., Rovo, A., Schears, R., Shah, A., Agrawal, V., Ahmed, A., Ahmed, I., Ali, A., Aljurf, M., Alkhateeb, H., Beitinjaneh, A., Bhatt, N., Buchbinder, D., Byrne, M., Callander, N., Fahnehjelm, K., Farhadfar, N., Gale, R. P., Ganguly, S., Hildebrandt, G. C., Horn, E., Jakubowski, A., Kamble, R. T., Law, J., Lee, C., Nathan, S., Penack, O., Pingali, R., Prasad, P., Pulanic, D., Rotz, S., Shreenivas, A., Steinberg, A., Tabbara, K., Tichelli, A., Wirk, B., Yared, J., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. E., Shaw, B. E., Valdes-Sanz, N. 2018

    Abstract

    Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.

    View details for PubMedID 30521975

  • Ocular graft-versus-host disease after hematopoietic cell transplantation: expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Inamoto, Y., Valdes-Sanz, N., Ogawa, Y., Alves, M., Berchicci, L., Galvin, J., Greinix, H., Hale, G. A., Horn, B., Kelly, D., Liu, H., Rowley, S., Schoemans, H., Shah, A., Stanghellini, M. T., Agrawal, V., Ahmed, I., Ali, A., Bhatt, N., Byrne, M., Chhabra, S., DeFilipp, Z., Fahnehjelm, K., Farhadfar, N., Horn, E., Lee, C., Nathan, S., Penack, O., Prasad, P., Rotz, S., Rovo, A., Yared, J., Pavletic, S., Basak, G. W., Battiwalla, M., Duarte, R., Savani, B. N., Flowers, M. E., Shaw, B. E., Petricek, I. 2018

    Abstract

    Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

    View details for DOI 10.1016/j.bbmt.2018.11.021

    View details for PubMedID 30481594

  • Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplant. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Norkin, M., Shaw, B. E., Brazauskas, R., Tecca, H. R., Leather, H. L., Gea-Banacloche, J., Kamble, R., DeFilipp, Z., Jacobsohn, D. A., Ringden, O., Inamoto, Y., Kasow, K., Buchbinder, D., Shaw, P., Hematti, P., Schears, R., Badawy, S. M., Lazarus, H. M., Bhatt, N., Horn, B., Chhabra, S., Page, K., Hamilton, B., Hildebrandt, G. C., Yared, J. A., Agrawal, V., Beitinjaneh, A., Majhail, N., Kindwall-Keller, T., Olsson, R. F., Schoemans, H., Gale, R. P., Ganguly, S., Ahmed, I., Schouten, H. C., Liesveld, J., Khera, N., Steinberg, A., Shah, A. J., Solh, M., Marks, D. I., Rybka, W., Aljurf, M., Dietz, A. C., Gergis, U., George, B., Seo, S., Flowers, M. E., Battiwalla, M., Savani, B. N., Riches, M. L., Wingard, J. R. 2018

    Abstract

    BACKGROUND: We analyzed late fatal infections (LFI) in allogeneic stem cell transplant (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research.METHODS: We analyzed the incidence, infection types and risk factors contributing to LFI in 10336 adult and 5088 pediatric subjects surviving ≥2 years after first HCT without relapse.RESULTS: Among 2245 adult and 377 pediatric subjects who died, infections were a primary or contributory cause of death in 687(31%) and 110(29%) subjects, respectively. At 12 years post-HCT cumulative incidence of LFIs was 6.4 % (95% confidence interval[CI]:5.8-7.0%) in adults as compared with 1.8% (95%CI:1.4-2.3%) in pediatric subjects, p<0.001. In adults, the two most significant risks for developing LFI were increasing age (20-39, 40-54 and ≥ 55 vs 18-19 years) with hazard ratio (HR) of 3.12 (95%CI:1.33-7.32), 3.86 (95%CI:1.66-8.95) and 5.49 (95%CI:2.32-12.99) and a history of chronic GVHD (cGVHD) with ongoing immunosuppression 2 years post-HCT as compared to no history of GVHD with HR 3.87 (95%CI:2.59-5.78), respectively. In pediatric subjects, the three most significant risks for developing LFI were a history of cGVHD with (HR 9.49, 95%CI:4.39-20.51) or without (HR 2.7,95%CI:1.05-7.43) ongoing immunosuppression 2 years post-HCT as compared to no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function as compared to diagnosis of acute myeloid leukemia (AML) (HR 2.30, 95%CI:1.19-4.42) and age >10 years (HR 1.92, 95%CI:1.15-3.2).CONCLUSION: This study emphasizes the importance of continued vigilance for late infections after HCT and support strategies aimed to decrease the risk of cGVHD.

    View details for PubMedID 30287390

  • Infusion of Alloanergized Donor Lymphocytes after CD34-selected Haploidentical Myeloablative Hematopoietic Stem Cell Transplantation CLINICAL CANCER RESEARCH Davies, J. K., Brennan, L. L., Wingard, J. R., Cogle, C. R., Kapoor, N., Shah, A. J., Dey, B. R., Spitzer, T. R., de Lima, M., Cooper, L. J., Thall, P. F., Champlin, R. E., Nadler, L. M., Guinan, E. C. 2018; 24 (17): 4098–4109

    Abstract

    Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098-109. ©2018 AACR.

    View details for PubMedID 29769208

    View details for PubMedCentralID PMC6125184

  • Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT BONE MARROW TRANSPLANTATION Buchbinder, D., Kelly, D., Duarte, R. F., Auletta, J. J., Bhatt, N., Byrne, M., DeFilipp, Z., Gabriel, M., Mahindra, A., Norkin, M., Schoemans, H., Shah, A. J., Ahmed, I., Atsuta, Y., Basak, G. W., Beattie, S., Bhella, S., Bredeson, C., Bunin, N., Dalal, J., Daly, A., Gajewski, J., Gale, R., Galvin, J., Hamadani, M., Hayashi, R. J., Adekola, K., Law, J., Lee, C. J., Liesveld, J., Malone, A. K., Nagler, A., Naik, S., Nishihori, T., Parsons, S. K., Scherwath, A., Schofield, H., Soiffer, R., Szer, J., Twist, I., Warwick, A. B., Wirk, B. M., Yi, J., Battiwalla, M., Flowers, M. E., Savani, B., Shaw, B. E. 2018; 53 (5): 535–55

    Abstract

    Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

    View details for PubMedID 29343837

    View details for PubMedCentralID PMC5985976

  • Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. The New England journal of medicine Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., Armant, M., Dansereau, C., Lund, T. C., Miller, W. P., Raymond, G. V., Sankar, R., Shah, A. J., Sevin, C., Gaspar, H. B., Gissen, P., Amartino, H., Bratkovic, D., Smith, N. J., Paker, A. M., Shamir, E., O'Meara, T., Davidson, D., Aubourg, P., Williams, D. A. 2017; 377 (17): 1630-1638

    Abstract

    Background In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. Methods We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. Results A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. Conclusions Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

    View details for DOI 10.1056/NEJMoa1700554

    View details for PubMedID 28976817

  • Neurocognitive Dysfunction in Hematopoietic Cell Transplant Recipients: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Complications and Quality of Life Working Party of the European Group for Blood and Marrow Transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Kelly, D. L., Buchbinder, D. n., Duarte, R. F., Auletta, J. J., Bhatt, N. n., Byrne, M. n., Gabriel, M. n., Mahindra, A. n., Norkin, M. n., Schoemans, H. n., Shah, A. J., Ahmed, I. n., Atsuta, Y. n., Basak, G. W., Beattie, S. n., Bhella, S. n., Bredeson, C. n., Bunin, N. n., Dalal, J. n., Daly, A. n., Gajewski, J. n., Gale, R. P., Galvin, J. n., Hamadani, M. n., Hayashi, R. J., Adekola, K. n., Law, J. n., Lee, C. J., Liesveld, J. n., Malone, A. K., Nagler, A. n., Naik, S. n., Nishihori, T. n., Parsons, S. K., Scherwath, A. n., Schofield, H. L., Soiffer, R. n., Szer, J. n., Twist, I. n., Warwick, A. n., Wirk, B. M., Yi, J. n., Battiwalla, M. n., Flowers, M. E., Savani, B. n., Shaw, B. E. 2017

    Abstract

    Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

    View details for PubMedID 28939455

  • Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report. Biology of blood and marrow transplantation Chow, E. J., Anderson, L., Baker, K. S., Bhatia, S., Guilcher, G. M., Huang, J. T., Pelletier, W., Perkins, J. L., Rivard, L. S., Schechter, T., Shah, A. J., Wilson, K. D., Wong, K., Grewal, S. S., Armenian, S. H., Meacham, L. R., Mulrooney, D. A., Castellino, S. M. 2016; 22 (5): 782-795

    Abstract

    Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Children's Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

    View details for DOI 10.1016/j.bbmt.2016.01.023

    View details for PubMedID 26802323

    View details for PubMedCentralID PMC4826622

  • Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Morris, J., Rudebeck, M., Neudorf, S., Moore, T., Duerst, R., Shah, A. J., Graham, M., Aquino, V., Morris, C., Olsson, B. 2016

    Abstract

    Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 μg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-μg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.

    View details for DOI 10.1016/j.bbmt.2016.02.016

    View details for PubMedID 26968792

  • Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Ayas, M., Eapen, M., Le-Rademacher, J., Carreras, J., Abdel-Azim, H., Alter, B. P., Anderlini, P., Battiwalla, M., Bierings, M., Buchbinder, D. K., Bonfim, C., Camitta, B. M., Fasth, A. L., Gale, R. P., Lee, M. A., Lund, T. C., Myers, K. C., Olsson, R. F., Page, K. M., Prestidge, T. D., Radhi, M., Shah, A. J., Schultz, K. R., Wirk, B., Wagner, J. E., Deeg, H. J. 2015; 21 (10): 1790-1795

    Abstract

    A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT.

    View details for DOI 10.1016/j.bbmt.2015.06.012

    View details for PubMedID 26116087

  • Unrelated donor Hematopoietic Stem Cell Transplantation for the treatment of non-malignant genetic diseases: An alemtuzumab based regimen is associated with cure of clinical disease; earlier clearance of alemtuzumab may be associated with graft rejection. American journal of hematology Abdel-Azim, H., Mahadeo, K. M., Zhao, Q., Khazal, S., Kohn, D. B., Crooks, G. M., Shah, A. J., Kapoor, N. 2015

    Abstract

    Purpose Hematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUD), offers potentially curative therapy for patients with non-malignant genetic diseases. In this pilot study conducted from 2006-2014, we report the outcomes of 15 patients with non-malignant genetic diseases who received a myeloablative regimen with a reduced cyclophosphamide dose, adjunctive serotherapy and MUD HSCT [intravenous alemtuzumab (52mg/m(2) ), busulfan (16mg/kg), fludarabine (140mg/m(2) ) and cyclophosphamide (105mg/kg)]. Graft-versus-host-disease (GVHD) prophylaxis consisted of tacrolimus/cyclosporine and methylprednisolone. Findings Median (range) time to neutrophil engraftment (>500 cells/µL) and platelet engraftment (>20,000/mm(3) ) were 15 (12 - 28) and 25 (17 - 30) days respectively. At a median follow-up of 2 (0.2-5.4) years, the overall survival (OS) was 93.3% (95% CI: 0.61 - 0.99) and disease-free survival (DFS) was 73.3% (95% CI: 0.44 - 0.89). Among this small sample, earlier alemtuzumab clearance was significantly associated with graft rejection (p = 0.047), earlier PHA response (p =0.009) and a trend toward earlier recovery of recent thymic emigrants (RTE) (p = 0.06). Conclusion This regimen was associated with durable donor engraftment and relatively low rates of regimen related toxicity (RRT); future alemtuzumab pharmacokinetic studies may improve outcomes, by allowing targeted alemtuzumab clearance to reduce graft rejection and promote more rapid immune reconstitution. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ajh.24141

    View details for PubMedID 26242764

  • A Reduced-Toxicity Regimen Is Associated with Durable Engraftment and Clinical Cure of Nonmalignant Genetic Diseases among Children Undergoing Blood and Marrow Transplantation with an HLA-Matched Related Donor. Biology of blood and marrow transplantation Mahadeo, K. M., Weinberg, K. I., Abdel-Azim, H., Miklos, D. B., Killen, R., Kohn, D., Crooks, G. M., Shah, A. J., Kharbanda, S., Agarwal, R., Kapoor, N. 2015; 21 (3): 440-444

    Abstract

    Blood and marrow transplantation (BMT) is a standard curative therapy for patients with nonmalignant genetic diseases. Myeloablative conditioning has been associated with significant regimen-related toxicity (RRT), whereas reduced-intensity conditioning regimens have been associated with graft failure. In this prospective pilot trial conducted at 2 centers between 2006 and 2013, we report the outcome of 22 patients with nonmalignant genetic diseases who were conditioned with a novel reduced-toxicity regimen: i.v. busulfan (16 mg/kg), alemtuzumab (52 mg/m(2)), fludarabine (140 mg/m(2)), and cyclophosphamide (105 mg/kg). The median age of the study population was 3.5 years (range, 5 months to 26 years). No cases of sinusoidal obstruction syndrome, severe or chronic graft-versus-host disease (GVHD), or primary graft failure were reported. Median time to neutrophil engraftment (>500 cells/μL) and platelet engraftment (>20K cells/μL) were 19 (range, 12 to 50) and 23.5 (range, 14 to 134) days, respectively. The median length of follow-up was 3 years (range, .2 to 6.3). The overall survival rates were 95% at 100 days (95% confidence interval, .72 to .99) and 90% at 6 years (95% confidence interval, .68 to .98). RRT and chronic GVHD are significant barriers to BMT for patients with nonmalignant genetic diseases. This alemtuzumab-based reduced-toxicity regimen appears to be promising with durable engraftment, effective cure of clinical disease, low rates of RRT, and no observed chronic GVHD.

    View details for DOI 10.1016/j.bbmt.2014.11.005

    View details for PubMedID 25459642

  • Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report. Supportive care in cancer Effinger, K. E., Migliorati, C. A., Hudson, M. M., McMullen, K. P., Kaste, S. C., Ruble, K., Guilcher, G. M., Shah, A. J., Castellino, S. M. 2014; 22 (7): 2009-2019

    Abstract

    Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2 years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children's Oncology Group.An English literature search for oral and dental complications of childhood cancer treatment was undertaken via MEDLINE and encompassed January 1975 to January 2013. Proposed guideline content based on the literature review was approved by a multi-disciplinary panel of survivorship experts and scored according to a modified version of the National Comprehensive Cancer Network "Categories of Consensus" system.The Children's Oncology Group oral-dental panel selected 85 relevant citations. Childhood cancer therapy may impact tooth development, salivary function, craniofacial development, and temporomandibular joint function placing some childhood cancer survivors at an increased risk for poor oral and dental health. Additionally, head and neck radiation and hematopoietic stem cell transplantation increase the risk of subsequent malignant neoplasms in the oral cavity. Survivors require routine dental care to evaluate for potential side effects and initiate early treatment.Certain childhood cancer survivors are at an increased risk for poor oral and dental health. Early identification of oral and dental morbidity and early interventions can optimize health and quality of life.

    View details for DOI 10.1007/s00520-014-2260-x

    View details for PubMedID 24781353

  • Avascular Necrosis of Bone after Allogeneic Hematopoietic Cell Transplantation in Children and Adolescents BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Li, X., Brazauskas, R., Wang, Z., Al-Seraihy, A., Baker, K. S., Cahn, J., Frangoul, H. A., Gajewski, J. L., Hale, G. A., Hsu, J. W., Kamble, R. T., Lazarus, H. M., Marks, D. I., Maziarz, R. T., Savani, B. N., Shah, A. J., Shah, N., Sorror, M. L., Wood, W. A., Majhail, N. S. 2014; 20 (4): 587-592

    Abstract

    We conducted a nested case-control study within a cohort of 6244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents after allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States, and had survived ≥ 6 months from transplantation. Overall, 160 patients with AVN and 478 control subjects matched by year of transplant, length of follow-up and transplant center were identified. Patients and control subjects were confirmed via central review of radiology, pathology, and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender, and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared with patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with nonmalignant diseases and those who had received reduced-intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression after hematopoietic cell transplantation for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication.

    View details for DOI 10.1016/j.bbmt.2013.12.567

    View details for PubMedID 24388803

  • Cytokine and chemokine patterns across 100 days after hematopoietic stem cell transplantation in children. Biology of blood and marrow transplantation DiCarlo, J., Agarwal-Hashmi, R., Shah, A., Kim, P., Craveiro, L., Killen, R., Rosenberg-Hasson, Y., Maecker, H. 2014; 20 (3): 361-369

    Abstract

    We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory "signature" provided by a multicytokine assay may be predictive.

    View details for DOI 10.1016/j.bbmt.2013.11.026

    View details for PubMedID 24316459

  • Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans BLOOD Candotti, F., Shaw, K. L., Muul, L., Carbonaro, D., Sokolic, R., Choi, C., Schurman, S. H., Garabedian, E., Kesserwan, C., Jagadeesh, G. J., Fu, P., Gschweng, E., Cooper, A., Tisdale, J. F., Weinberg, K. I., Crooks, G. M., Kapoor, N., Shah, A., Abdel-Azim, H., Yu, X., Smogorzewska, M., Wayne, A. S., Rosenblatt, H. M., Davis, C. M., Hanson, C., Rishi, R. G., Wang, X., Gjertson, D., Yang, O. O., Balamurugan, A., Bauer, G., Ireland, J. A., Engel, B. C., Podsakoff, G. M., Hershfield, M. S., Blaese, R. M., Parkman, R., Kohn, D. B. 2012; 120 (18): 3635-3646

    Abstract

    We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

    View details for DOI 10.1182/blood-2012-02-400937

    View details for Web of Science ID 000311624800007

    View details for PubMedID 22968453

    View details for PubMedCentralID PMC3488882

  • Neurocognitive Function of Patients with Severe Combined Immunodeficiency IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Shah, A. J., Kohn, D. B. 2010; 30 (1): 143-?

    Abstract

    Hematopoietic stem cell transplantation (HSCT) has offered a curative approach for treating patients with severe combined immunodeficiency (SCID). However, HSCT may have long-term effects on some of these patients. This article reviews the literature regarding long-term neurocognitive function of patients who have received HSCT for SCID, including the effect of disease-specific characteristics, psychosocial factors, being a chronically ill child, and transplant-related factors.

    View details for DOI 10.1016/j.iac.2009.10.003

    View details for Web of Science ID 000279717200011

    View details for PubMedID 20113891

  • Long-Term Neurocognitive Function of Pediatric Patients with Severe Combined Immune Deficiency (SCID): Pre- and Post-Hematopoietic Stem Cell Transplant (HSCT) JOURNAL OF CLINICAL IMMUNOLOGY Lin, M., Epport, K., Azen, C., Parkman, R., Kohn, D. B., Shah, A. J. 2009; 29 (2): 231-237

    Abstract

    Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe combined immunodeficiency (SCID). The purpose of this study was to evaluate long-term neurodevelopment of patients with SCID following myeloablative chemotherapy and HSCT.Sixteen pediatric patients diagnosed with SCID were tested using the Bayley Scales of Infant Development and the validated Vineland Adaptive Behavior Scales (VABS) pre- and 1-year post-HSCT. Three years post-HSCT, there were 11 patients available for testing and four patients available 5 years post-HSCT. Patients greater than 3 years of age were administered the Wechsler Preschool and Primary Scale of Intelligence. Both raw scores and scaled scores were analyzed.There was a significant decrease 1 year post-HSCT in the Bayley Mental Developmental Index (MDI) [92.5 (pre) vs. 70.81 (1 year post), p < 0.0001] and the VABS [99.73 (pre) vs. 79.87 (1 year post), p = <0.0001]. There was a significant decrease over time in the MDI [95.00 (pre) vs. 72.64 (1 year post) vs. 71.82 (3 years post), p < 0.0001], but no significant change between 1 and 3 years post-HSCT. There was no change in the Bayley Psychomotor Development Scale (PDI) [82.4 (pre) vs. 84.8 (1 year post), p = 0.68]. The PDI scores decreased over time [86.29 (pre) vs. 86 (1 year post) vs. 74.14 (3 years post), p = 0.045]. Although there was a decrease in scaled scores, there was not a loss of skills. Analysis of raw scores showed that there was an increase in the raw test scores, which indicated that these children acquired developmental skills, but at a slower rate than normal infants and toddlers. Younger children had a more significant decrease in adaptive scores compared with older children.These findings may reflect the effects of the isolation and prolonged hospitalization that characterizes the immediate post-transplant period. Patients miss out on social interactions and learning opportunities that normally occur at their respective stages of development. These restrictions keep patients from acquiring developmentally appropriate cognitive skills as well as gross and fine motor developmental milestones. Longitudinal follow-up will be important to quantify acquisition of skills.

    View details for DOI 10.1007/s10875-008-9250-z

    View details for Web of Science ID 000263894600011

    View details for PubMedID 18807155

  • Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Shah, A. J., Epport, K., Azen, C., Killen, R., Wilson, K., De Clerck, D., Crooks, G., Kapoor, N., Kohn, D. B., Parkman, R., Weinberg, K. I. 2008; 30 (6): 411-418

    Abstract

    Neurocognitive function of pediatric patients is of great concern after hematopoietic stem cell transplantation (HSCT). We evaluated the neurocognitive function of pediatric patients pre-HSCT, 1, 3, and 5 years post-HSCT. All patients had a hematologic malignancy and received therapy to their central nervous system. Healthy siblings were tested as a comparison group. Pediatric patients with a hematologic malignancy did not have a significant decrease in their cognitive function before HSCT compared with their siblings except in areas of academic achievement. Our study population had significant declines in visual motor skills and memory test scores within the first year post-HSCT. By 3 years post-HSCT, there was an improvement in the visual motor development scores and memory scores, but there were new deficits in verbal skills. By 5 years post-HSCT, there were progressive declines in verbal skills (P=0.005), performance skills (0.04), and new deficits seen in long-term verbal memory scores (0.04). On the basis of the raw scores, most of these tests showed that patients had an inability to acquire new skills at a rate comparable to their age-matched healthy peers. However, long-term memory scores showed definite declines. The greatest decline in neurocognitive function occurred in those patients who received cranial irradiation either as part of their initial therapy or as part of their HSCT conditioning. Pediatric patients who received HSCT for hematologic malignancies have neurocognitive deficiencies that are both acute and chronic. Although some patients have acute deficits that appear and improve over time, other patients have progressive declines in neurocognitive function that are chronic.

    View details for Web of Science ID 000256535200001

    View details for PubMedID 18525456

  • The effects of Campath 1H upon graft-versus-host disease, infection, relapse, and immune reconstitution in recipients of pediatric unrelated transplants BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Shah, A. J., Kapoor, N., Crooks, G. M., Weinberg, K. I., Azim, H. A., Killen, R., Kuo, L., Rushing, T., Kohn, D. B., Parkman, R. 2007; 13 (5): 584-593

    Abstract

    Graft-versus-host disease (GVHD) is a cause of serious morbidity and mortality in >50% of recipients of unrelated hematopoietic stem cell transplantation (HSCT). We performed a trial using Campath 1 H pre- and post-HSCT in an attempt to decrease the incidence of GVHD without increasing the risk of infection or relapse. Patients were retrospectively compared to a population of patients who received antithymocyte globulin (ATG) pre- and post-HSCT. Twenty-seven patients were evaluated for this study. Fourteen patients received Campath 1H and 13 patients received ATG. Demographics of patients who received Campath 1H consisted of 9 males and 5 females, with a median age of 13 years (3-17.8 years). Thirteen patients received unrelated bone marrow and 1 patient received unrelated PBSC. Demographics of patients receiving ATG consisted of 9 males, 4 females with a median age of 7.4 years (21 months-19 years). Twelve patients received unrelated bone marrow and 1 patient received unrelated PBSC. Diagnoses were similar between the 2 groups. Patients who received Campath1H received a total dose of 52 mg/m(2) pre-HSCT and 20 mg/m(2) post-HSCT. Patients who received ATG received a total dose of 60 mg/kg pre-HSCT and 100 mg/kg post-HSCT. GVHD prophylaxis and supportive care measures were similar in both groups, including aggressive antimicrobial therapy. There was a significant difference in the incidence of severe (grade III and grade IV) GVHD between the 2 groups (Campath [0 of 14] versus ATG [6 of 13], P = .006). Among the patients who were transplanted for leukemia, there was no significant difference between the 2 groups in terms of relapse (Campath [2 of 14] versus ATG [4 of 9], P = 0.16). The 100-day survival between the 2 groups was not significantly different. Patients receiving Campath 1H had the presence of CD3(+) T cells (>30 cells/mL) in their peripheral blood later than in those who received ATG (64.5 days [Campath 1H] versus 27days [ATG], P = .001). The median time to the development of a normal PHA response occurred later in the Campath 1H arm (283 days[(Campath 1H] versus 88 days [ATG], P = .0001). The median time to an antigen specific response also occurred later in those receiving Campath 1H (365 days [Campath 1H] versus 150 days [ATG], P = .004). There was no significant difference between the 2 groups in terms of fungal or viral infections. Campath 1H is effective in decreasing the incidence of GVHD without increasing the risk of relapse. Although there is a significant delay in immune reconstitution, there was no increase in infectious complications or relapse in recipients of Campath 1H. Further studies are warranted to assess if a lack of difference in infection rates are still demonstrated in larger cohorts.

    View details for DOI 10.1016/j.bbmt.2007.01.076

    View details for Web of Science ID 000246252600010

    View details for PubMedID 17448918