Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study.

A prospective longitudinal study of cognitive and psychosocial functioning in pediatric hematopoietic stem cell transplant (HSCT) patients was conducted on three occasions: pre-HSCT, 1 year post-HSCT, and 2 years post-HSCT. In contrast to the previous hypothesis that cognitive declines would occur as a result of HSCT treatment, it was hypothesized that (1) global cognitive functioning (IQ scores), as well as specific areas would remain stable over time; (2) pre-transplant functioning would be predictive of later functioning; and (3) age would be negatively related to cognitive functioning. Based on previous research it was further hypothesized: that (4) while declines in psychosocial functioning might be seen at 1 year, functioning would improve by 2 years. 153 children and adolescents were evaluated pre-HSCT and at 1 year, with 2 year data available for 74 children. Longitudinal analyses of Wechsler IQ data were completed on 100 children (longitudinal exact test) and 52 children (repeated measures analysis of variance. Results of cognitive assessment indicated (1) stability of IQ scores over time; and (2) that the strongest predictor was pre-HSCT cognitive functioning. Psychosocial assessment results indicated: (1) a low prevalence of behavioral and social problems; (2) stability in functioning over time; (3) pre-HSCT functioning strongly predictive of later functioning.

Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program.

Human leukocyte antigen (HLA)-identical sibling bone marrow transplantation is an effective treatment for Wiskott-Aldrich syndrome. However, most children with this disease lack such donors and many patients receive transplants from alternative donors. This study compared outcomes of HLA-identical sibling, other related donor, and unrelated donor transplantation for Wiskott-Aldrich syndrome. The outcome of 170 transplantations for Wiskott-Aldrich syndrome, from 1968 to 1996, reported to the International Bone Marrow Transplant Registry and/or National Marrow Donor Program were assessed. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. Multivariate proportional hazards regression was used to compare outcome by donor type and identify other prognostic factors. Most transplant recipients were younger than 5 years (79%), had a pretransplantation performance score greater than or equal to 90% (63%), received pretransplantation preparative regimens without radiation (82%), and had non-T-cell-depleted grafts (77%). Eighty percent received their transplant after 1986. The 5-year probability of survival (95% confidence interval) for all subjects was 70% (63%-77%). Probabilities differed by donor type: 87% (74%-93%) with HLA-identical sibling donors, 52% (37%-65%) with other related donors, and 71% (58%-80%) with unrelated donors (P =.0006). Multivariate analysis indicated significantly lower survival using related donors other than HLA-identical siblings (P =.0004) or unrelated donors in boys older than 5 years (P =.0001), compared to HLA-identical sibling transplants. Boys receiving an unrelated donor transplant before age 5 had survivals similar to those receiving HLA-identical sibling transplants. The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children.

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.

Effect of T cell subset dose on outcome of T cell-depleted bone marrow transplantation.

T cell depletion using the murine monoclonal antibody (moAb) T10B9 is unique in that the T cell receptor (TCR)gamma delta bearing subset is relatively spared compared to the TCR alpha beta + subset. We evaluated the probabilities of engraftment, acute and chronic graft-versus-host disease (GVHD), relapse, and survival in 273 recipients of marrow T cell depleted using T10B9. Sixty-two patients received marrow from an HLA-identical sibling, 54 patients received partially matched related donor marrow and 157 patients received unrelated donor marrow. Limiting dilution analysis (LDA) was used to estimate total clonable T cell dose in all patients and a modified LDA using moAb-coated immunomagnetic beads was used to estimate TCR alpha beta +, CD4+, and CD8+ T cells in a subset of patients. TCR gamma delta + cell dose was estimated by flow cytometry. Cox proportional hazards regression models were used to assess the impact of T cell subset dose/kg of body weight on outcome. We found a significant association of TCR gamma delta + T cell dose (P = 0.004), but not TCR alpha beta + T cell dose or total clonable T cell dose, with the probability of engraftment. TCR alpha beta +, CD4+, CD8+ and total clonable T cell dose were significantly associated (P < 0.001) with the risks of grade 2-4 acute GVHD in recipients of marrow from related donors but not in recipients of marrow from unrelated donors. Neither total clonable T cell dose nor any T cell subset dose was found to be significantly associated with chronic GVHD, relapse or survival. The results confirm preclinical studies showing TCR gamma delta + T cells promote engraftment. TCR gamma delta + T cells are not associated with an increased risk of acute GVHD while TCR alpha beta T cells are associated with acute GVHD but not engraftment in recipients of marrow grafts T cell depleted using T10B9. These findings support the hypothesis that T cell subsets differentially contribute to alloengraftment and GVHD.

Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults.

Alternative donor bone marrow transplantation (BMT) to treat severe aplastic anaemia (SAA) in children and young adults has been complicated by high rates of graft rejection and severe graft-versus-host disease (GVHD). We hypothesized that increased immunosuppression combined with T-cell depletion of the marrow graft would enable successful use of unrelated donor BMT in this disease. Preconditioning consisted of cytosine arabinoside, cyclophosphamide, and total body irradiation (TBI). T-cell depletion was with the anti-CD3 antibody T10B9. GVHD prophylaxis consisted of cyclosporine A. 28 previously transfused patients were transplanted. Nine donor/recipient pairs were HLA matched. As of 1 January 1996, 15/28 (54%) patients are alive, transfusion independent and well with a range of follow-up of 13 months to 8 years (median 2.75 years). Fatalities include all three patients with nonengraftment and all three patients with grade III/IV GVHD. Other fatalities were due to infections or therapy-related toxicity. The incidence >or= grade II acute GVHD was 28%. These data show that in children with SAA who have failed immunosuppression, unrelated donor BMT offers a reasonable hope of long-term survival.

Unrelated bone marrow donor transplants for children with leukemia or myelodysplasia.

Allogeneic bone marrow transplantation is the treatment of choice for many childhood leukemias. The donor of choice-an HLA matched sibling-is only available about 30% of the time. Unrelated donors are an alternative choice. In this report, we describe the results of unrelated donor bone marrow transplants (BMT) in 50 children with leukemia (25 acute lymphoblastic leukemia [ALL], 3 acute myeloid leukemia [AML], 3 juvenile chronic myelogenous leukemia [JCML], 10 chronic myeloid leukemia [CML]) or myelodysplastic syndrome (MDS; 9). The median age of the 31 male and 19 female patients was 9 years (range 2 to 18). Only 13 patients were serologically matched at HLA-A, B, DR, and DQ with their donors; 6 of these were reactive in mixed lymphocyte culture. The other 37 patients were mismatched for one (36 patients) or more (1 patient) HLA antigens. Pretransplant conditioning included cytosine arabinoside, cyclophosphamide, fractionated total body irradiation (TBI) (with lung, liver, and more recently, kidney shielding), and methylprednisolone. High-risk patients also received busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of T-cell depletion with IgM monoclonal antibody T10B9 plus complement and posttransplant cyclosporine-A. Forty-nine patients (98%) engrafted. Median times to greater than 500 polymorphonuclear leukocytes (PMN)/microL and greater than 25,000 platelets/microL were 18 and 20 days, respectively. Acute GVHD > or = grade II occurred in 16 patients (33%); 13 (81%) of these died. Chronic GVHD developed in 30 of 40 patients at risk, but was extensive in only 5. Event-free survival (EFS) for all patients was 44% +/- 7% (median follow-up was 49 months), and overall survival was 50 +/- 7%. Patients with low-risk disease (ALL or AML in first or second remission and CML in chronic phase) had a better EFS than children with high-risk disease (60% v 34%, P = .07). There was no significant difference in EFS between patients who were serologically matched with their donors (46%) and those who were partially mismatched (43%) (P = .97). These data compare favorably with published reports for children transplanted with HLA-matched sibling donors and should encourage earlier consideration of unrelated donor BMT in children with leukemia or myelodysplasia.

Progressive immunodeficiency and fatal pneumonitis associated with human herpesvirus 6 infection in an infant.

Human herpesvirus 6 (HHV-6), an important opportunistic pathogen in immunocompromised patients, causes fatal pneumonitis, encephalitis, and bone marrow suppression. Its ability to infect and destroy T lymphocytes may allow it to synergize with the human immunodeficiency virus in the destruction of lymphoid tissues in patients with AIDS. We describe herein an infant who had an immunodeficiency associated with thymic atrophy and severe T lymphocytopenia who developed fatal pneumonitis due to HHV-6. Dense and disseminated infection of T lymphocytes with HHV-6 was also documented. In the absence of any other documented cause of immunodeficiency, we hypothesize that congenital infection of this infant with HHV-6 may have caused progressive destruction of her cellular immune system, leading to the fatal pneumonitis. Thus, HHV-6 infection may have been the cause of both her immunodeficiency and her fatal opportunistic infection.

Prevention and treatment of acute graft-vs.-host disease.

PURPOSE: Acute graft-vs.-host disease (aGVHD), a relatively common complication of allogeneic bone marrow transplantation, is mediated by graft-derived T-lymphocytes that recognize host antigens not expressed by the donor. Clinical manifestations of aGVHD involve the skin, gut, and liver with varying degrees of severity. Strategies for prevention and treatment of aGVHD are reviewed. PATIENTS AND METHODS: The assessment of the degree of disparity in the human leukocyte antigen (HLA) type of donor and recipient pairs using refined serologic and molecular biologic testing is necessary for the prevention of severe aGVHD. T-lymphocyte depletion of the bone marrow graft removes the effector cells for aGVHD, but is associated with other transplant related morbidity. Immunosuppressive agents, which are used for prevention, are the basis of treatment for aGVHD. RESULTS: Recently developed techniques for tissue typing may result in the more accurate prediction of aGVHD in donor and recipient pairs. Despite the use of careful donor selection, graft T-lymphocyte depletion, and vigorous prophylactic immunosuppression, aGVHD occurs in a large number of bone marrow transplant patients. Treatment of aGVHD with standard immunosuppressive agents is effective in most cases. Newly developed immunosuppressive agents are being studied for the treatment of aGVHD which responds poorly to therapy. CONCLUSIONS: Acute graft-vs.-host disease is responsible for significant morbidity in bone marrow transplant patients. Newer approaches to the prevention and treatment of this disease are currently being evaluated.

A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.

The c-myb proto-oncogene encodes a sequence-specific DNA-binding protein. To better understand its normal biological function, we have altered the c-myb gene by homologous recombination in mouse embryonic stem cells. Resulting homozygous c-myb mutant mice displayed an interesting phenotype. At day 13 of gestation these mice appeared normal, suggesting that c-myb is not essential for early development. By day 15, however, the mutant mice were severely anemic. Analysis indicated that embryonic erythropoiesis, which occurs in the yolk sac, was not impaired by the c-myb alteration. Adult-type erythropoiesis, which first takes place in the fetal liver, was greatly diminished in c-myb mutants, however. Additional hematopoietic lineages were similarly affected. These results are compatible with a role for c-myb in maintaining the proliferative state of hematopoietic progenitor cells.

A modified method for human bone marrow filtration prior to bone marrow transplantation.

A technique is described for filtering harvested bone marrow using disposable materials, namely a 4 x 4 inch piece of sterile gauze that is gently packed into the barrel of a 60-ml plastic disposable syringe, which is connected directly to a blood collection bag. The filtration of marrow directly into the collection bag eliminates additional filtration steps and therefore may potentially reduce the incidence of inadvertent microbial contamination. In this study we describe this filtering technique and compare it to the method described by Thomas and Storb. Numbers of granulopoietic progenitors (CFU-GM) and erythropoietic progenitors (BFU-E), total white cell counts, percentage of cells positive for the CD3 (OKT3) lymphocyte surface membrane marker, and volume changes were studied following filtration by each method. The two techniques were shown to be comparable in terms of these parameters. Furthermore, when compared with historical controls, this method resulted in a reduced incidence of microbial contamination compared to filtration using successive stainless steel screens.