Staged informed consent for a randomized clinical trial in childhood leukemia: impact on the consent process.

BACKGROUND: Children Cancer Group (CCG) 1991 is the first childhood acute lymphoblastic leukemia trial within CCG that allowed the utilization of a staged approach to the consent process. METHODS: One hundred and forty subjects participated in the Project on Informed Consent which compared the primary outcome measures in the consent process of patients enrolled in CCG-1991 with those enrolled in other CCG leukemia studies. RESULTS: The parents' trust scores were higher for the CCG-1991 compared with other protocols. Eighty percent of parents enrolled in CCG-1991 understood the distinction between the randomized clinical trial and the standard treatment arm, compared with 62.5% in the other studies, P = 0.05. Multiple other outcome measures suggested a positive impact from staged informed consent. CONCLUSIONS: Our results suggest that a consent process with a staged approach can help investigators obtain a more truly informed consent. Future research is needed to confirm the benefits of the staged approach to the informed consent process.

Is there a potential role for serum cardiac troponin I as a marker for myocardial dysfunction in pediatric patients receiving anthracycline-based therapy? A pilot study.

Serum cardiac troponin I (cTnI) levels have been reported to have high specificity and sensitivity to acute myocardial infarction and coronary ischemic syndromes in adult patients. Our goal was to evaluate the usefulness of serum cTnI in the early diagnosis of cardiac injury from anthracyclines, and to compare these values with echocardiographic findings of cardiac dysfunction. In this prospective study, children being treated on several Children's Cancer Group protocols underwent measurement of shortening fraction (SF), ejection fraction (EF), and serum cTnI levels prior to anthracycline therapy. Sequential serum cTnI levels were then measured along with regularly scheduled echocardiograms with progressively increasing doses of anthracyclines. Fifteen children with median age of 5.75 years (range, 15 months to 15.5 years) at diagnosis were evaluated. Anthracycline doses ranged from 11.72 mg/kg (in patients < 3 years of age) to 375 mg/m2. All but one patient had normal cTnI levels. His level measured at 1.7 ng/ml after 315 mg/m2, but was normal on follow-up testing. Initial SF ranged from 32 to 48%, and EF from 60 to 80%. On follow-up, SF and EF ranged from 30 to 41% and 55 to 70%, respectively. Both SF and EF were significantly lower (p < 0.001) as compared to the initial values. Despite this, all patients remained clinically asymptomatic from the cardiac standpoint. We did not observe elevations of serum cTnI levels in clinically asymptomatic children who received anthracycline therapy up to doses of 375 mg/m2. Does this mean that cardiac injury has not occurred? The possibility of assay sensitivity and the timing of serum sampling and echocardiograms may be important. In addition, larger sample size or longer follow-up may be helpful to determine if higher doses or symptomatic patients potentially have elevations in cTnI levels.

One course versus two courses of antithymocyte globulin for the treatment of severe aplastic anemia in children.

PURPOSE: The aim of the therapeutic trials was to optimize the treatment of severe aplastic anemia (SAA) and moderate aplastic anemia in children who lack a suitable bone marrow donor, using immunosuppressive therapy in the most effective combination and dose. PATIENTS AND METHODS: Two sequential therapeutic trials for the treatment of severe and moderate aplastic anemia in children were conducted by 10 institutions. The treatment protocols included antithymocyte globulin (ATG), prednisone, and cyclosporine A (CSA); patients entered on the first protocol, 0190 (ATG X 2), were given two courses of ATG, and those enrolled on the second protocol, 0190B (ATG X 1), were given only one course of ATG. Ten patients were evaluable on ATG X 2. All patients had SAA; three had hepatitis-induced severe aplastic anemia (HI-SAA). Twelve patients were evaluable on ATG X 1; all had SAA, one of whom had HI-SAA. RESULTS: Seven of 10 patients on ATG X 2 responded, and eight of 12 patients treated on ATG X 1 responded. CONCLUSION: Treatment with immunosuppressive therapy using ATG, CSA, and prednisone was very well tolerated. The response rates in both protocols were similar, and results compare favorably with those of previous therapeutic trials, suggesting that a second course of ATG is not necessary.

Antithymocyte globulin, cyclosporine, and prednisone for the treatment of severe aplastic anemia in children. A pilot study.

PURPOSE: The aim of the therapeutic trial was to try to optimize the treatment of severe and moderate aplastic anemia in children who lack a suitable bone marrow donor using the most successful available drugs, with the least amount of side effects. PATIENTS AND METHODS: A pilot study for the treatment of severe aplastic anemia in children was conducted by four institutions. The treatment protocol included antithymocyte globulin (ATG), prednisone, and cyclosporine A. Twelve patients were enrolled, and 11 were evaluable. All patients had severe aplastic anemia (SAA); three had hepatitis-induced severe aplastic anemia (HI-SAA). RESULTS: Of 11 evaluable patients, eight have responded with normalization of their blood counts. Two of the three patients with HI-SAA responded to the therapy. CONCLUSION: The results of our pilot study compare favorably with previous therapeutic trials. All the patients who responded achieved complete response, i.e., restoration of blood counts to within the normal range.

In utero engraftment of fully H-2-incompatible versus congenic adult bone marrow transferred into nonanemic or anemic murine fetal recipients.

We have established a murine in utero bone marrow transplantation model system and have investigated the effects of donor strain differences, cell dose, and the number of injections on murine fetal survival and engraftment rates. In a series of experiments, 1221 nonanemic C57BL/6 fetuses were injected transplacentally on day 11 of gestation with 10(6) non-T-depleted adult bone marrow cells (BMC) from C57BL/6-CAST (congenic), BALB/c and DBA/1 (allogeneic) strains without recipient conditioning. Overall fetal survival was 45%, with a 4% engraftment rate in 475 evaluable day 5 newborns. Engrafted newborns initially had up to 75-100% donor peripheral blood cell engraftment, particularly with DBA/1 BMC. Surprisingly, a significantly (P < 0.05) higher incidence of engraftment was observed using allogeneic (5.2%) as compared with congenic donors (0.7%). However, engraftment in all groups was transient since engrafted recipients studied > or = 6 weeks post-natally had nondetectable levels of donor cells. In contrast, engraftment of congeneic marrow into anemic, stem cell-defective Wv/Wv recipients lead to a higher incidence (40%) of engraftment that persisted for > or = 6 weeks, increasing in the level of engraftment over time. Additional studies were performed in an attempt to further increase the incidence and permanence of engraftment. Neither doubling the cell dose nor doubling the number of injections improved engraftment rates in recipients of allogeneic bone marrow. Similarly, pretreatment of congeneic donors with 5-fluorouracil 4 days prior to harvesting marrow was not effective in increasing engraftment. Despite the inability to detect donor cells > or = 6 weeks postallografting, 2 of 10 evaluable recipients engrafted with DBA/1 BMC had specific and permanent (> 6 months observation time) tolerance to the donor skin graft with an intact capacity to reject third-party grafts. Thus short-term engraftment of allogeneic adult marrow stem cells can be successfully accomplished in a proportion of nonanemic fetal recipients. Engraftment of allogeneic donor cells can also lead to induction of a degree of tolerance in a proportion of recipients at maturity. These data form the basis of future studies directed toward understanding the mechanisms involved in in utero and postnatal marrow graft resistance, which will ultimately lead to designing strategies that will further enhance the permanence of engraftment with the use of adult marrow cells.

Severe aplastic anemia preceding acute lymphoblastic leukemia.

BACKGROUND: Bone marrow aplasia preceding acute lymphoblastic leukemia (ALL) is a rare condition that usually affects children. The ALL generally follows the recovery of normal blood counts and most commonly occurs within 6 months of the onset of aplasia. The case of a patient with severe aplastic anemia is reported in whom ALL developed 15 months after the initial diagnosis of aplastic anemia. A literature search found 23 cases of ALL after a period of aplasia or hypoplasia. This patient's disease, however, was different from all previously reported ones. The severe aplasia lasted 15 months before being followed by ALL. There was no recovery of blood counts before the onset of ALL. METHODS: A review of the literature found 23 case reports in which aplasia or hypoplasia preceded ALL; these patients also had pancytopenia of the peripheral blood. Excluded from this review were patients whose bone marrow was hypoplastic, but who did not have pancytopenia because these did not have "aplastic anemia" as their initial disease. RESULTS: Analysis of the reported patients showed that most were girls 10 years of age or younger. There was an overwhelming prevalence of fever, which in several instances, might have had an infectious cause. ALL most commonly occurred within 6 months of the aplasia and usually followed the recovery of normal blood counts. CONCLUSIONS: Patients with ALL after a prolonged period of aplasia have several common characteristics including female sex, young age, and the prevalence of fever, often associated with an infectious illness. ALL usually follows the recovery of blood counts and occurs within 6 months of the onset of aplasia. The pathophysiology of this patient's disease(s) is still unclear. He could have had two unrelated disorders or a two-step leukemic process that followed a stem cell "insult." This patient had an antecedent hepatitis A infection 3 months before aplasia occurred. However, the authors were unable to identify with certainty any other event that might have caused additional bone marrow injury.