Renee Madden

A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation.

As survivors of pediatric allogeneic hematopoietic stem cell transplantations (HSCTs) increase in number, it is increasingly important to evaluate their well-being. We conducted this prospective cohort study to evaluate the cumulative incidence and risk factors for late sequelae of HSCT. Comprehensive surveillance tests were performed annually on every participant, regardless of signs and symptoms, to obtain accurate information on the time-of-onset of each late event to allow hazard function analyses. All participants included in this report had been followed for at least 3 years after HSCT. With a median follow-up of 9 years and a current age of 18.5 years, only 20 of the 155 participants (13%) had no late sequelae; 18 survivors (12%) had 1 chronic health condition, 71 (46%) had 2-4 conditions, and 46 (30%) had 5-9 conditions. Risk factors for increasing number of chronic conditions included young age at the time of HSCT, female sex, high radiation dose, and history of chronic graft-versus-host disease. The cumulative incidence at 10 years for common late events was as follows (ordered by the median time-of-onset): osteonecrosis 13.8%, chronic renal insufficiency 26.8%, hypothyroidism 45.1%, growth hormone deficiency 31.2%, female hypogonadism 57.4%, osteopenia 47.7%, cataracts 43.4%, pulmonary dysfunction 63.2%, and male hypogonadism 20.3%. Coexistence of multiple late sequelae was common in HSCT survivors. Our findings provide a basis for more effective patient counseling, optimal surveillance, and early intervention. Abbreviations: ACTH = adrenocorticotropin, CI = confidence intervals, DLCO = diffusing capacity of carbon monoxide, FEV1 = forced expiratory volume in 1 second, FSH = follicle-stimulating hormone, FT4 = free thyroxine, FVC = forced vital capacity, GVHD = graft-versus-host disease, HSCTs = hematopoietic stem cell transplantations, IGFBP3 = insulin-like growth factor binding protein-3, LH = luteinizing hormone, OR = odds ratio, PFT = pulmonary function test, TBI = total body irradiation, TLC = total lung capacity, TSH = thyroid stimulating hormone.

Prophylaxis of Pneumocystis carinii pneumonia with atovaquone in children with leukemia

Despite extensive studies of atovaquone in human immunodeficiency virus (HIV)‐infected patients, there is little information about its efficacy as a prophylactic agent for Pneumocystis carinii pneumonia (PCP) in pediatric patients with cancer. Therefore, a retrospective analysis was conducted to determine the incidence of PCP in pediatric patients who received prophylactic atovaquone during treatment for acute leukemia.

Total and active rabbit antithymocyte globulin (rATG;Thymoglobulin) pharmacokinetics in pediatric patients undergoing unrelated donor bone marrow transplantation.

Rabbit antithymocyte globulin (rATG; Thymoglobulin) is currently used to prevent or treat graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation (HSCT). The dose and schedule of rATG as part of the preparative regimen for unrelated donor (URD) bone marrow transplantation (BMT) have not been optimized in pediatric patients. We conducted a prospective study of 13 pediatric patients with hematologic malignancies undergoing URD BMT at St. Jude Childrens Research Hospital from October 2003 to March 2005, to determine the pharmacokinetics and toxicities of active and total rATG. The conditioning regimen comprised total body irradiation (TBI), thiotepa, and cyclophosphamide (Cy); cyclosporine (CsA) and methotrexate (MTX) were administered as GVHD prophylaxis. Patients received a total dose of 10 mg/kg rATG, and serial blood samples were assayed for total rATG by enzyme linked immunosorbent assay (ELISA) and active rATG by florescein activated cell sorting (FACS). We found that our weight-based dosing regimen for rATG was effective and well tolerated by patients. The half-lives of total and active rATG were comparable to those from previous studies, and despite high doses our patients had low maximum concentrations of active and total rATG. There were no occurrences of grade iii-iv GVHD even in patients having low peak rATG levels, and the overall incidence of grade II GVHD was only 15%. None of the patients had serious infections following transplantation. These data support the use of a 10 mg/kg dose of rATG in children with hematologic malignancies because it can be administered without increasing the risk of graft rejection, or serious infection in pediatric patients with a low rate of GVHD. These conclusions may not apply to patients with nonmalignant disorders.

High White Blood Cell Concentration in the Peripheral Blood Stem Cell Product Can Induce Seizures during Infusion of Autologous Peripheral Blood Stem Cells

Seizures as a complication of the infusion of autologous peripheral blood stem cells (PBSC) are rare. Seizures during infusion of autologous PBSC in 3 of our patients prompted us to review our cell therapy and cytapheresis protocols and procedures. We retrospectively analyzed 159 adult patients collected between January 2006 and July 2009. Patients were collected on either the COBE Spectra (Caridian BCT, Lakewood, CO) cell separator (n = 85) or Fresenius AS (Fresenius Kabi AG, Bad Homburg, Germany) 104 cell separator (n = 74) and mobilized with granulocyte-colony stimulating factor (G-CSF) alone (n = 47), G-CSF and Plerixafor (n = 36), or G-CSF and chemotherapy (n = 76). Patient characteristics (including age, weight, number of collections, volume processed, disease type, and mobilization strategy) did not differ significantly between the COBE and Fresenius cohorts, and adverse effects from infusion were similar except for 3 of 159 patients who experienced seizures upon infusion of PBSC; all 3 were collected on the COBE and had PBSC product white blood cell (WBC) counts of 590 × 10(3)/μL or above. We prospectively correlated WBC counts midcollection, with final WBC counts to identify products with high WBC concentration during cytapheresis. Fifty-one patients had 66 cytapheresis procedures using the COBE, with WBC counts midway and at the end of collection of 287 × 10(3) ± 150/μL and 273 × 10(3) ± 144/μL, respectively. Mid-WBC therefore correlated with WBC at the end of the collection. Finally, we prospectively collected mid-WBC from 65 patients who underwent 80 PBSC collections between June 2009 and January 2010 to identify products with midcollection WBC concentration >450 × 10(3)/μL. In those cases, additional autologous plasma was collected at the time of collection to dilute the final product before cryopreservation. Patients who received diluted products experienced no delays in engraftment and no additional seizure episodes occurred.

Clinical Utility of Computed Tomography Screening of Chest, Abdomen, and Sinuses before Hematopoietic Stem Cell Transplantation: The St. Jude Experience

All allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) recipients at St. Jude Childrens Research Hospital undergo pre-HSCT computed tomography (CT) of the sinuses, chest, and abdomen because they are at significant risk for opportunistic infections. We studied whether this extensive routine imaging is warranted to detect infection despite the risk of additional radiation exposure. We reviewed the medical records of all children receiving allo- and auto-HSCT at St. Jude in 2004 and 2005. Of the 184 eligible patients who received 187 transplants, 131 received allografts and 56 autografts. Solid tumors and lymphomas were removed from the final analysis of the chest and abdomen CT as this imaging is typically warranted as part of disease restaging; thus, 111 allogeneic participants were included in this analysis. Both auto- and allo-recipients were evaluated by sinus CT and included in this final analysis. Most allo- and auto-HSCT recipients (> or =80%) did not have sinus, pulmonary, cardiac, or gastrointestinal symptoms; >85% of the evaluable allo-recipients had no prior fungal infection. Eighty-eight allo- and 31 auto-HSCT recipients had abnormal sinus CT findings, all unrelated to the underlying disease. Sixty-two (55.9%) of the allo-recipients had normal chest CT and 85 (76.6%) had normal abdominal CT. Of the 18 allo-recipients who began new therapy based on these findings, only 2 (11.1%) were related to chest CT findings and the other 16 were related to sinus findings. Our findings suggest that pre-HSCT routine CT imaging of the abdomen may not be warranted in a subset of allogeneic recipients who are asymptomatic and without previous infectious findings. Thus, these patients may be spared unnecessary radiation exposure. Recipients undergoing auto-HSCT or allo-HSCT for lymphomas or solid tumors will routinely undergo chest and abdominal CT imaging as part of their disease evaluation. The decision to perform chest CT should be made judiciously based on a careful history and physical examination. Sinus imaging, which was frequently abnormal, may be justified in all patients to plan post-HSCT care.

A novel approach for quantification of KIR expression in healthy donors and pediatric recipients of hematopoietic SCTs.

The killer cell Ig-like receptor (KIR) expression repertoire may offer valuable information for hematopoietic SCT (HSCT). We designed a quantitative KIR RNAtype assay and used it to determine KIR gene expression in healthy donors and patients before HSCT. The specificity of the assay was ensured by specific primers and by electrophoretic distinction of PCR products of unique length. In 87 healthy donors, the KIR repertoire was broadly distributed (32 categories of profiles). There was an overall trend toward inverse correlation of KIR expression level and donor age. Age affected mainly the activating KIR families. Leukemia patients showed lower KIR expression before transplantation than healthy donors. Stem cell mobilization caused a transient increase of KIR expression. We conclude that KIR expression differs quantitatively with age and primary disease and is transiently altered by stem cell recruitment and selection.

Supportive Care: Myelosuppression

The success of aggressive, curative anticancer therapies in pediatric oncology is possible only with intensive supportive-care measures. For example, antimicrobial prophylaxis can reduce infection rates in children undergoing myelosuppressive chemotherapy. Likewise, preemptive, broad-spectrum antibiotic therapy given as treatment for fever and neutropenia has been shown to reduce the mortality rate in this patient population. Furthermore, blood-product support is essential during periods of marrow suppression, and hematopoeitic growth factors, such as granulocyte colony-stimulating factor and erythropoietin, can be used to reduce the duration of pancytopenia. These interventions work together with therapeutic interventions to provide optimal outcomes for pediatric patients with cancer.

Supportive Care: Symptom Control

Chemotherapy-induced emesis, poor nutrition, and pain are primary concerns with patients undergoing cancer therapy. Major advances have been made in the control of these symptoms. For example, new antiemetic agents are available that can effectively reduce nausea and vomiting after chemotherapy. Nutritional screening and early intervention, especially via the enteral route, are being used in children who experience weight loss and anorexia. A better understanding of the mechanisms of cancer pain and acceptance of the use of analgesics, by physicians and parents, also facilitate optimal symptom control in pediatric patients with cancer.