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Robertson Parkman

Publications and source records attributed to Robertson Parkman.

11 recordsLinked to original sources
PubMed2006

Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.

A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.

Adenosine Deaminase↗
PubMed2006

Successful immune reconstitution decreases leukemic relapse and improves survival in recipients of unrelated cord blood transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is established therapy for selected patients with acute leukemia. After transplantation, antileukemic immune responses are believed to eliminate residual leukemia cells and decrease the likelihood of relapse. However, the clinical effect of successful antigen-specific immune reconstitution after HSCT on the likelihood of leukemic relapse and overall survival is not known. Pediatric recipients of unrelated cord blood transplants who underwent transplantation for acute leukemia were sequentially evaluated for their development of antigen-specific T-lymphocyte immunity to herpes viruses. The clinical effect of a positive antigen-specific response on relapse-free survival was determined. The presence of an antigen-specific response resulted in a relapse-free survival advantage (P = .0001), which was primarily due to a decrease in leukemic relapse (P = .003). Proportional hazards modeling for time to relapse and time to relapse or death defined 3 variables that were strongly associated with a poor outcome: female gender, poor remission status before transplantation, and negative antigen-specific T-lymphocyte proliferation. Notably neither acute nor chronic graft-versus-host disease had any effect on the incidence of leukemic relapse. Successful antigen-specific immune reconstitution after unrelated cord blood transplantation results in decreased leukemic relapse and improved overall survival.

Adolescent↗
PubMed2006

Antigen-specific T-lymphocyte function after cord blood transplantation.

It has not been possible to determine the singular contribution of naive T lymphocytes to antigen-specific immunity after hematopoietic stem cell transplantation (HSCT), because of the confounding effects of donor-derived antigen-specific T lymphocytes present in most hematopoietic stem cell (HSC) products. Because umbilical cord blood contains only naive T lymphocytes, we longitudinally evaluated the recipients of unrelated cord blood transplantation (UCBT) for the presence of T lymphocytes with specificity for herpesviruses, to determine the contribution of the naive T lymphocytes to antigen-specific immune reconstitution after HSCT. Antigen-specific T lymphocytes were detected early after UCBT (herpes simplex virus on day 29; cytomegalovirus on day 44; varicella zoster virus on day 94). Overall, 66 of 153 UCBT recipients developed antigen-specific T lymphocytes to 1 or more herpesviruses during the evaluation period. The likelihood of developing antigen-specific T lymphocyte function was not associated with immunophenotypic T lymphocyte reconstitution, transplant cell dose, primary disease, or acute and chronic graft-versus-host disease. These results indicate that naive T lymphocytes present in the HSC inoculum can contribute to the generation of antigen-specific T-lymphocyte immunity early after transplantation.

Adolescent↗
PubMed2005

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Adenosine Deaminase↗
PubMed2005

Successful hematopoietic stem cell transplantation for Niemann-Pick disease type B.

Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother. At the time of transplantation, she had severe pulmonary disease. After her first HSCT, she developed graft failure. Five years after her second HSCT, her sphingomyelinase levels are within normal levels, she has no pulmonary symptoms, and aside from persistent graft versus host disease, she is doing well.

Child, Preschool↗
PubMed2004

Busulfan and cyclophosphamide as a conditioning regimen for pediatric acute lymphoblastic leukemia patients undergoing bone marrow transplantation.

Bone marrow transplantation (BMT) has become the standard therapy for children with relapsed acute lymphoblastic leukemia. The authors report their experience with histocompatible BMT for 52 children with acute lymphoblastic leukemia conditioned with a non-total body irradiation (TBI) regimen using busulfan and cyclophosphamide (Bu/Cy). The efficacy and long-term toxicity of the Bu/Cy regimen were determined. Overall survival was 35%. One-year, 3-year, and 7-year event-free survival rates were 54%, 33%, and 23%, respectively. Of the 52 BMT recipients, 26 relapsed. Thirteen of the relapsed patients received a second BMT and three were surviving as of this writing. The most frequent cause of death was leukemia relapse. An initial remission duration of less than 18 months was a factor in decreasing the event-free survival. The Bu/Cy regimen was well tolerated, with minimal transplant-related mortality. Neurocognitive function was tested before BMT and 1 year after BMT. When 1-year posttransplant neurocognitive test scores were compared with pretransplant scores, there was no decrease. However, there was a significant decrease in the pretransplant neurocognitive test scores in BMT recipients compared with their normal siblings. The use of Bu/Cy as a conditioning regimen for BMT does not appear to affect posttransplant neurocognitive function. Other long-term side effects, such as endocrinopathies and secondary malignancies, were also minimal. These data show that the Bu/Cy regimen is well tolerated, but the overall survival rate remains low.

Adolescent↗
PubMed2003

Antigen-specific immune function after hematopoietic stem cell transplantation.

Hematopoietic stem cell recipients are characterized by an immunodeficiency of varying severity and duration. The present review focuses on the antigen-specific function of recipients with the hypothesis that the acquisition of antigen-specific function is predictive of the recipient's capacity to resist lethal infection with environmental pathogens.

Antigens↗
PubMed2002

Second hematopoietic stem cell transplantation in pediatric patients: overall survival and long-term follow-up.

Despite potent intensive conditioning regimens, hematopoietic stem cell transplantation (HSCT) may fail because of either relapse of the malignancy or the rejection of the graft. We report on 27 pediatric patients who received a second HSCT from an allogeneic donor for relapsed malignancy or graft failure. One-year, 5-year, and 10-year probabilities of survival for all patients were 53%, 36%, and 24%, respectively. Twenty patients received second HSCTs for relapsed malignancy, of whom 6 were alive and disease free at the time of this report. Seven patients received a second HSCT for graft failure, of whom 3 were alive and well as of this report. Twenty-five patients were tested for immune reconstitution following their second HSCT. Sixteen patients developed antigen-specific T-lymphocyte responses; the median time to development of antigen-specific responses was 13 months. There was no significant neurocognitive decline in patients tested 1 to 3 years following their second HSCT. Endocrine evaluations revealed deficiencies in growth hormone (7 patients), gonadal function (3 patients), and thyroid function (2 patients). Three patients developed significant abnormalities of tooth development, including absence of secondary teeth. These results show that a second HSCT offers curative therapy for selected pediatric patients whose first HSCT failed. Although toxicity is considerable following a second transplantation, the major causes of mortality continue to be relapse and infection.

Adolescent↗
PubMed2000

Bone Marrow Transplantation for Non-Malignant Disease.

This article reviews the experience in hematopoietic stem cell transplantation (HSCT) for non-malignant disease. HSCT has long been applied as treatment of life-threatening congenital immunodeficiency and metabolic diseases. In Section I, Dr. Parkman reviews that experience for severe combined immunodeficiency, Wiscott-Aldrich syndrome, hyper IGM syndrome, Chédiak-Higashi disease and hereditary lymphohistiocytosis. The value of HSCT in genetic metabolic diseases such as osteopetrosis, osteogenesis imperfecta and the storage diseases are reviewed. In Section II, Dr. Walters reviews the experience over the last decade with allogeneic stem cell transplantation in patients with thalassemia major and sickle cell disease. In Section III, Dr. Sullivan reviews the more recent investigations using stem cell transplantation in patients with advanced autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, multiple sclerosis and juvenile rheumatoid arthritis. The pathogenesis and outcome with conventional care of these patients, the selection criteria and current results for HSCT, and the future directions in clinical research and patient care using this modality are addressed.

Journal Article↗