M.J. Cowan

PEDIATRIC ACQUIRED IMMUNODEFICIENCY SYNDROME

Approximately 40 to 50 infants and children with similar epidemiologic, clinical, and laboratory features of AIDS have been described. The occurrence of significant numbers of patients with PAIDS in geographic areas that are associated with similar risk factors and clinical features of AIDS suggests a common cause. Immunologic evaluation reveals hypergammaglobulinemia, decreased or absent antibody responses after immunization, normal to decreased T-cell numbers, decreased helper/suppressor cell ratios, and abnormal results of functional studies of T-cells. None of the patients described has the clinical or laboratory features of well-established congenital immunodeficiency disorders. No consistent viral agent has been documented except for antibody to ARV and HTLV III. The frequent finding of T-cell abnormalities in the mothers of infants with PAIDS is in contrast to the absence of such abnormalities in the mothers of infants with congenital immunodeficiency disorders. Future studies in PAIDS should be directed toward uncovering the etiology and risk factors as well as determining the response to treatment with various methods of immunologic reconstitution.

Autoimmune hemolytic anemia in patients with SCID after T cell-depleted BM and PBSC transplantation

We report a high incidence (19.5%) of autoimmune hemolytic anemia (AIHA) in 41 patients with SCID who underwent a T cell-depleted haploidentical transplant. Other than infections, AIHA was the most common post-transplant complication in this patient cohort. Clinical characteristics and treatment of eight patients who developed AIHA at a median of 8 months after the first T cell-depleted transplant are presented. All patients had warm-reacting autoantibodies, and two of eight had concurrent cold and warm autoantibodies. Clinical course was most severe in two patients who had cold and warm autoantibodies. Five patients received specific therapy for AIHA. Successful taper off immunosuppressive therapy for AIHA coincided with T cell reconstitution. Delayed reconstitution of T cell immunity, due to T cell depletion, immunosuppressive conditioning and CsA, as well as paucity of regulatory T cells, are the likely explanations for the occurrence of AIHA in our patient cohort. Screening of the population at risk may prevent morbidity and mortality from AIHA.

Safety of the live, attenuated varicella vaccine in pediatric recipients of hematopoietic SCTs

VZV is an important cause of morbidity and mortality among patients after hematopoietic SCT (HSCT). There is controversy surrounding the use of the live attenuated varicella vaccine (LAVV) in this population due to concerns that the immunization may cause VZ-related disease. The Blood and Marrow Transplant (BMT) group at the University of California, San Francisco (UCSF) Childrens Hospital has been recommending the LAVV for immunocompetent HSCT patients since 1995. We retrospectively examined the incidence of post-immunization complications attributable to the LAVV in pediatric patients after HSCT. We also reported seroconversion rates when possible. Among 68 recipients of the LAVV after HSCT, 3 (4.4%; 95% confidence interval (CI)=1.0–12.7%) experienced mild-to-moderate symptoms potentially attributable to vaccination, and there were no severe reactions. Among 28 patients analyzed for seroconversion, 18 (64.3%; 95% CI=45.8–79.4%) seroconverted, 3 (10.7%; 95% CI 2.9–28.0%) possibly seroconverted and 7 (25.0%; 95% CI=12.4–43.6%) failed to seroconvert. It appears safe to administer the LAVV to immunocompetent patients after HSCT. Prospective studies are needed to more accurately determine rates of vaccine complications, efficacy and immunologic responses to vaccination.

Veno-occlusive disease of the liver in children with solid tumors undergoing autologous hematopoietic progenitor cell transplantation: a high incidence in patients with neuroblastoma

We retrospectively analyzed the incidence and risk factors for veno-occlusive disease (VOD) in 83 consecutive children with solid tumors, who underwent autologous blood or bone marrow (BM) transplantation at UCSF between 1992 and 2000. Forty-one patients were diagnosed with neuroblastoma and 42 had another solid tumor (Ewings sarcoma, soft tissue sarcomas, germ cell tumors, etc). Patients with neuroblastoma were more likely than patients with other solid tumors (ST) to be ⩽7 years of age, to have a decreased serum albumin level, and to have received abdominal radiation and surgery prior to transplant. Patients with neuroblastoma received a different conditioning regimen and a purged stem cell product. Twenty patients (24%) developed VOD. VOD was self-limited in 15 (75%) patients and severe in five (25%) patients. Univariate analysis identified the following risk factors for VOD: diagnosis of neuroblastoma (odds ratio 6.1, P < 0.01), abdominal radiation (odds ratio 4.1, P < 0.01), abdominal surgery (odds ratio 4.1, P < 0.01), and age ⩽7 years of age (odds ratio 3.3, P = 0.02). Disease status at transplant, intensity of previous chemotherapy, conditioning regimen, progenitor cell source, ALT, AST, albumin level, renal function prior to transplant, or use of amphotericin, growth-factor or heparin during transplant, did not affect the incidence of VOD. On multivariate analysis, only the diagnosis of neuroblastoma remained significant (odds ratio 7.8, P = 0.03). Larger studies of patients with neuroblastoma are necessary in order to confirm our findings and better define the risk factors for VOD development in neuroblastoma patients.Bone Marrow Transplantation (2002) 29, 409–415. doi:10.1038/sj.bmt.1703393

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders

We performed quantitative PCR-based serial chimerism testing of whole blood (WB) and CD3+ cells and retrospectively correlated the results of chimerism tests and the risk of graft loss in children undergoing transplant for non-malignant disorders. Twenty-four children were included in this study. All patients initially engrafted; subsequently, 12% lost the graft, 21% achieved complete donor chimerism and 67% had mixed chimerism (MC). Patients underwent delayed taper of cyclosporine (CsA) if they had MC. Overall survival was 87±7% (s.d.) at 5-years post transplant, and it was not affected by chimerism status. Both WB and CD3+ chimerism showed significant fluctuations with a peak in autologous cell signal occurring at a median of 7 months for WB and 2 months for CD3+ cells. Initial post transplant chimerism percentage in either WB or CD3+ lineage was not related to graft loss. Increasing MC to >30% host cells was seen in 33% of patients, and it was related to increased risk of graft loss, as previously published. However, 63% of children with increasing MC did not lose their graft. Additional studies of post transplant chimerism are required to improve our ability to accurately identify children at risk of graft loss following transplant for non-malignant disorders.

Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML

The major problems with busulfan/cyclophosphamide (Bu/Cy)-containing conditioning regimens are acute toxicities and graft failure. To decrease acute toxicities, we have prospectively evaluated a reduced intensity conditioning (RIC) regimen using targeted dosing of i.v. busulfan, fludarabine, and rabbit ATG (Bu/Flu/rATG) in children with diagnoses that historically would have been conditioned with Bu/Cy regimens. Nineteen pediatric patients were enrolled in the study. The donors included HLA-matched and one antigen-mismatched unrelated volunteers (n=11), unrelated cord blood (n=1), and related donors (n=7). Four patients developed graft failure, which occurred between 1 and 8.5 months post transplant. All four of them underwent a second transplantation and 3/4 are alive without evidence of disease. The mean follow-up of living patients is 29.5±s.d. 11 months. Despite excellent 2-year post-transplant overall survival (89±s.d.7%) and event-free survival (74±s.d.10%), the study was closed prematurely due to high graft failure rate (21%). Receiving a transplant from a mismatched unrelated donor was identified as a risk factor for graft failure. The Bu/Flu/rATG RIC regimen was very well tolerated, resulted in excellent overall survival, and provided sustained engraftment in patients undergoing transplant from matched sibling and unrelated donors. However, it did not provide sustained engraftment in the majority of children with nonmalignancies undergoing mismatched unrelated donor transplants.

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation

Background: X‐linked hyper‐IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow‐up of a large sample of patients with XHIGM to (1) compare long‐term overall survival and general well‐being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan‐Meier method compared with log‐rank tests and modeled by using proportional hazards regression. Results: Twenty‐eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow‐up and vital status information. Sixty‐seven (38%) patients received HCT. The average follow‐up time was 8.5 ± 7.2 years (range, 0.1‐36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987‐1995; the hazard ratio was significantly less than 1 for diagnosis years 1995‐1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2‐10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft‐versus‐host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964‐2013). However, survivors treated with HCT experienced somewhat greater well‐being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Haploidentical related-donor hematopoietic cell transplantation in children using megadoses of CliniMACs-selected CD34 + cells and a fixed CD3 + dose

We conducted a prospective phase II trial utilizing the CliniMACs system to perform CD34+-cell selection of PBSCs from haploidentical donors to evaluate engraftment and hematoimmunological reconstitution. In total, 21 children with hematological malignancies or nonmalignant conditions underwent conditioning with 1200 cGy TBI, thiotepa, fludarabine and Thymoglobulin. Patients received megadoses of CD34+ cells (median: 22 × 106/kg) with a fixed dose of 3 × 104/kg CD3+ cells/kg, and engraftment occurred in 90% with prompt recovery of neutrophils and platelets. Grade II acute GVHD (aGVHD) was seen in 32% (95% confidence interval (CI), 15–54%) of evaluable patients, there was no grade III–IV aGVHD, and chronic extensive GVHD was seen in 35% (95% CI, 17–59%) of patients. The estimated 2-year EFS was 62% (95% CI, 48–83%) with a median survivor follow-up of 49 months (range: 18–119 months). Patients with nonmalignant diseases had an estimated 2-year EFS of 100% (95% CI, 56–100%) and patients with malignancies in remission had an estimated 2-year EFS of 56% (95% CI, 22–89%). Megadose CD34+ cells with a fixed CD3+ cell dose from haploidentical related donors resulted in good outcomes for pediatric patients with nonmalignant diseases and those with malignant diseases transplanted in remission.

Total body irradiation and bone marrow transplantation for immunodeficiency disorders in young children

Congenital immunodeficiency disorders such as severe combined immunodeficiency disease (SCID), Wiskott-Aldrich syndrome, and Chediak-Hegashi syndrome are almost uniformly fatal with most children dying before age one. Allogeneic bone marrow transplant (BMT) is the treatment of choice. Few of these children have matched donors. We use bone marrow processing techniques that allow us to utilize marrow from the parents. Children who lack HLA-identical donors are offered haploidentical, T-cell depleted parental BMTs. Some of these children do not have an immune deficiency severe enough to allow durable engraftment of processed mismatched bone marrow. Successful engraftment may necessitate the use of immunosuppression. Total body irradiation (TBI) is part of our intensive conditioning regimen for children with Wiskott-Aldrich and Chediak-Hegashi syndrome and most children with SCID who have undergone an unsuccessful prior mismatched, T-cell depleted BMT, or who have a high likelihood of donor marrow rejection based on pre-transplant immune function testing. TBI is considered extremely toxic therapy in infancy, with little information available on the acute and chronic effects. The 10 children presented in this report are among the youngest to have received TBI. Five patients were 2 to 6 months of age when they received TBI. The conditioning regimen for all patients was; antithymocyte globulin (25 mg/kg/day, x 3 days), cyclophosphamide (60 mg/kg/day, x 2 days), and TBI. 7.0 Gy TBI was given as a single dose AP-PA at approximately 15 cGy/min. Half value blocks shielded the brain, eyes and lungs. Six of 10 children were alive from 7 to 72 months post transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT

Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.