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10511Background: CCS are at a 10-fold increased risk of CNS SNs. Cranial radiation (CRT) for primary cancer increases the risk; dose-risk relation with CRT is linear. The substantial burden of CNS SN-related morbidity presents an unmet need for identifying high-risk patients to guide targeted interventions. We present a risk prediction model to address this gap. Methods: CCS with CNS SNs (cases: n=82) matched to CCS without CNS SNs (controls: n=228; matched on primary cancer diagnosis (dx), year of dx, race/ethnicity and follow-up), contributed germline DNA for genotyping 43 previously published candidate genes (97 SNPs). Risk prediction models were derived sequentially: Base Model (age at primary cancer dx, gender), Clinical Model (Base Model + CRT [Y/No]), Final Model (Clinical Model + SNPs). Receiver operating characteristic analysis was used to evaluate predictive utility of Final Model in assessing CNS SN risk. Two risk groups were derived using predicted values (high risk: ≥0.1; low risk

Background: Adequateexposure to oral 6MP during maintenance is critical to sustain durable remissions. We have previously shown that poor systemic exposure to 6MP (as measured by poor adherence to oral 6MP) is associated with increased risk of relapse (JCO 30[17]:2094-101; Blood 124[15]:2345-53). Accurate assessment of 6MP intake is therefore critical to ensure timely interventions. Self-report is a convenient and inexpensive method to monitor 6MP intake in the clinical setting; however, literature in the non-oncology setting indicates that self-report is subject to over-reporting, and the extent of over-reporting is directly related to the number of missed doses. The accuracy of self/parent-report of 6MP intake during ALL maintenance is not known. We address this issue by comparing self-reported 6MP intake to electronic monitoring, and identify predictors of over-reporting of prescribed 6MP intake. Methods: Participants included 416 children with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. 6MP intake was measured electronically using the Medication Event Management System (MEMS - objective record), which recorded the dates/times of each 6MP bottle opening over 4 study months per patient (28 days/month). The patient (or parent if MEMS report: ≥5 days/month for >50% of study months) and "others." Logistic regression examined characteristics (age at study, sex, race/ ethnicity, 6MP non-adherence [MEMs-based adherence rate Results: Median age at study entry was 6y (2-20); 36% were non-Hispanic white; 67% were male; 38.4% had high-risk disease; 40.4% were non-adherent to oral 6MP. Subjective vs objective 6MP intake: Mean (±SD) days of 6MP ingestion per month ranged from 25.8±5.3 to 26.1±4.5 by subjective reporting vs 22.8±6.4 to 25.4±4.5 by objective measurement (adjusted mean values by generalized estimating equations analysis, Figure 1A). The correlation between self-report and MEMS by study month ranged from 0.36 to 0.58 (Table). The difference between subjective and objective reporting was 0 for 39.6% patient-months; the difference was 0 for 52.7% patient-months (Figure 1B). A total of 50 (12%) patients were identified to be perfect reporters, 98 (23.6%) as over-reporters, and 64.4% as others.Predictors of over-reporting: Logistic regression modeling (adjusted for TPMT genotype, 6MP dose intensity and red cell TGN levels) identified the following independent predictors of over-reporting: i) Older age (Odds Ratio [OR]=1.07/y increase in patient age, 95% Confidence Interval [CI]=1.0-1.1, p=0.04); ii) Non-white race: Hispanic, OR=2.4, 95%CI=1.2-5.0, p=0.02); Asian, OR=3.1, 95%CI 1.2-8.3, p=0.02; African-American, OR=5.3, 95%CI 2.2-12.5, p Conclusions: Over-reporting of 6MP intake is common during maintenance therapy for childhood ALL. Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education. Subjective reporting of 6MP ingestion during maintenance therapy for childhood ALL may be unreliable, particularly in non-adherent patients, and should be used with caution. Table. 6MP ingestion by self-report vs. MEMS Study month Patients (N) Self-report (days)(mean, SD) MEMS (days)(mean, SD) Correlation p-value 1 275 26.1 (4.5) 25.4 (4.5) 0.58 Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Purpose Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. Patients and Methods One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. Results A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m2: reference; 1 to 100 mg/m2: odds ratio [OR], 1.65; 101 to 150 mg/m2: OR, 3.85; 151 to 200 mg/m2: OR, 3.69; 201 to 250 mg/m2: OR, 7.23; 251 to 300 mg/m2: OR, 23.47; > 300 mg/m2: OR, 27.59; Ptrend < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m2) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m2) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. Conclusion This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m2. Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.

Since 1975, there has been a dramatic increase in the survival rates of pediatric and older cancer patients, but adolescent and young adult (AYA) patients ages 15 to 40 years have not had a similar improvement. Data indicate a direct correlation between increased cure rates and clinical trial enrollment.The authors previously published data indicating inferior clinical trial enrollment when AYA patients were treated at an adult oncology center versus a pediatric oncology center. To address this deficit, a joint pediatric and adult AYA Oncology Program was established in July 2006 with the primary objective of improving outcomes by increasing therapeutic clinical trial enrollment in this population. Patients who were referred to that program from July 2006 through June 2010 were examined retrospectively to establish whether clinical trial enrollment increased compared with historic controls.Fifty-seven patients were referred to the program from 2006 to 2010 (range, 12-16 new patients per year). Eight patients were referred for consultation only and were not treated at the University of Pittsburgh Cancer Institute or Children's Hospital of Pittsburgh. Five of 22 patients (23%) who received treatment at the pediatric cancer center were enrolled onto a clinical trial, whereas 9 of 27 patients (33%) patients who received treatment at the adult cancer center were enrolled. There was superior trial participation compared with the previous 3 years for those shared AYA patients who were treated at the adult center (P.001).Data from this study demonstrated that establishing a unified AYA oncology program can lead to improved clinical trial enrollment for patients who are treated at medical oncology centers.

The study examined three issues that affect children being treated for cancer: ( I ) the relative aversiveness of two common diagnostic and treatment procedures, (2) the relationship between observed distress, age, and staff ratings of patients' behavior, and (3) the extent to which physical restraint during invasive procedures is related to the child's observed distress and staff ratings. Seventeen children treated for cancer were observed during diagnostic and treatment procedures. In addition, staff ratings of the children's cooperation and anxiety and the effects of restraint were collected. The results highlight the differential response of children to the two procedures as well as the potential utility of assessing the amount of physical restraint required.

Purpose Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. Patients and Methods Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. Results Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% ± 5.8%. CR1 duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MD) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% ± 11.3% and 77.7% ± 6.4% (P = .027), respectively. NCI high- versus standard-risk 4-year EFS was 51.4% ± 10.8% and 80.2% ± 6.3% (P = .0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P = .0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. Conclusion Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CR1 of 18 months or more. Novel strategies are needed for patients with CR1 of less than 18 months.

Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

Background: Exposure to oral 6MP for ~2 years is critical for durable remissions in children with ALL. We have previously shown that poor 6MP adherence (rates Methods: Participants included 441 patients with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. Adherence was measured using Medication Event Management System (MEMS) that recorded dates/times of each 6MP bottle opening for 6 mo/pt (58,086 patient-days of MEMS data). Average adherence rate (days MEMS bottle opened/days 6MP prescribed) over the 6m study period was computed to define non-adherence (adherence rate Results: Median age at diagnosis was 6y (2-20); 67% were males; 40.3% had high-risk disease. 43.8% of the patients were non-adherent. Pill-taking habits and non-adherence: Time-varying generalized estimating equations (adjusted for age at study, ethnicity/race, income, and parental education) identified the following predictors of non-adherence: i) Taking 6MP with dairy (Odds Ratio [OR]=1.9, 95% Confidence Interval [CI]=1.3-2.9, p=0.003); ii) Taking 6MP at varying times vs. non-varying times (OR=2.4, 95%CI=1.2-4.7, p=0.008); iii) No routine (OR=1.7, 95%CI=1.1-2.7, p=0.02). Crushing the pill vs. swallowing whole was less likely to be associated with non-adherence (OR=0.7, 95%CI=0.4-0.99, p=0.05) [Fig 1A].Pill-taking habits and relapse: A proportional sub-distribution hazards model (adjusted for time from start of maintenance, NCI risk group, cytogenetics, race/ethnicity, age at study, and adherence) demonstrated no association between pill-taking habits and relapse risk: i) 6MP with food (Hazard Ratio [HR]=0.7, 95%CI=0.3-1.9, p=0.5); ii) 6MP with dairy (HR=0.3, 95%CI=0.07-1.5, p=0.2); iii) Swallowing tablet whole vs. crushing/chewing (HR=0.8, 95%CI=0.3-2.1, p=0.7); iv) 6MP in the evening/night vs. morning/mid-day (HR=1.1, 95%CI=0.2-7.5, p=0.9); v) 6MP at varying times vs. non-varying times (HR=1.0, 95%CI=0.2-4.5, p=0.9) [Fig 1B].Pill-taking habits and DI-adjusted TGN levels: Among adherent patients, there was no association between DI- and age-adjusted TGN levels and: i) 6MP with food (p=0.5); ii) 6MP with dairy (p=0.7); iii) Swallowing 6MP whole vs. chewing/crushing (p=0.4); iv) 6MP in the morning/midday vs. evening/night (p=0.5); v) 6MP at varying times vs. non-varying times (p=0.5) [Fig 1C]. Conclusions: The association between non-adherence and certain pill-taking habits identifies a subgroup of patients that either did not receive appropriate instructions or did not adhere to them; our study was not designed to discern between the two scenarios. However, pill-taking habits were not associated with either relapse risk or TGN levels. These findings suggest that the commonly-practiced restrictions surrounding 6MP ingestion (i.e., taking only in the evening without food/dairy) might not influence outcome. Figure 1A Figure 1A. Figure 1B Figure 1B. Figure 1C Figure 1C. Disclosures Evans: St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.

10013 Background: We have previously shown that poor adherence (adherence rate

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P < .001, χ2). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Background Prolonged (∼2y) exposure to 6MP is associated with durable remissions in children with ALL. 6MP exerts cytotoxicity through conversion to thioguanine nucleotide (TGN) that is incorporated into DNA. Erythrocyte TGN concentration correlates with cytotoxicity. Systemic exposure to 6MP is influenced by: i) prescribed dose (dose intensity [DI]), ii) patient (pt) adherence, and iii) inherited capacity to metabolize 6MP by thiopurine methyltransferase (TPMT). Previous studies have shown the individual impact of these variables, but the contribution of each of these variable measured simultaneously in determining relapse risk is unknown – and was explored in the current study. Methods: We enrolled 744 pts in 1st remission and receiving oral 6MP (75 mg/m2/d) during maintenance. Monthly TGNs (∼6/ pt) yielded 3,953 measurements. 6MP DI (dose prescribed/ protocol dose) was ascertained for 113,682 days. TPMT genotyping classified pts as TPMT wild-type homozygotes (WT, 93.2%), heterozygotes (het, 6.7%) and homozygotes for deficient variants (def, 0.1%). Coefficient of variation (CV) was used to determine intra-individual variability in TGN (IQR=17.6-40.3), DI (3.2-28.2) and ANC (29.0-59.7). Using TGN CV% Disclosures: Evans: St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other. Relling:St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other.

Background Asparaginase is an important component of therapy for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, up to 30% of patients (pts) develop an allergy to Escherichia coli (E coli)–derived asparaginase. In those pts, Erwinia asparaginase (Erwinia), an antigenically distinct preparation derived from Erwinia chrysanthemi, can be used. Although Erwinia is typically administered intramuscularly (IM), intravenous (IV) asparaginase would offer a more convenient, less painful administration route. In an open-label, single-arm, multicenter, pharmacokinetic (PK) study, we evaluated IV administration of Erwinia in children and adolescents with ALL who developed hypersensitivity to E coli–derived asparaginase. Methods Pts (aged ≥1 to ≤30 years) with ALL or LBL who developed hypersensitivity (grade ≥2) to E coli–derived asparaginase were eligible for enrollment. Pts received Erwinia IV, 25,000 IU/m2/dose, on a Monday/Wednesday/Friday (M/W/F) schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in the original treatment plan. All other chemotherapy was continued per the original treatment plan. Blood samples were collected during the 1st treatment cycle, including predose, 5 min, 48 hrs and 72 hrs postdose. The primary study objective was to determine the proportion of pts who achieved nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hrs after dose 5 in cycle 1. Secondary objectives included determining the proportion of pts who achieved NSAA ≥0.1 IU/mL at 72 hrs after dose 6 in cycle 1 and the incidence of asparaginase-related toxicities. Only pts who completed 1 cycle of Erwinia were considered evaluable for NSAA assessment. Results Between November 2012 and June 2013, 30 pts were enrolled from 10 centers; 26 pts completed cycle 1. Twenty-three pts were evaluable for the primary NSAA endpoint (3 pts were not evaluable; 2 for PK data collected outside the protocol-specified window and 1 for nonadherence to the dosing schedule). Median age was 6.5 years (1-17 years), 63% were male, and 83% Caucasian. Predose NSAA levels were below the limit of quantification (defined as 0.0129 IU/mL) for nearly all (91%) pts. Of the 23 evaluable pts who completed cycle 1, 19 (83%) achieved NSAA levels ≥0.1 IU/mL at 48 hrs postdose 5, with mean ±SD NSAA 0.32 ±0.23 (Table 1). At 72 hrs postdose 6, 9 pts (45%) achieved NSAA levels ≥0.1 IU/mL (mean ±SD 0.088 ±0.076). Four pts discontinued Erwinia treatment before completing cycle 1; 3 for hypersensitivity and 1 for pancreatitis. The toxicity analysis included all 30 enrolled pts. The most common asparaginase-related toxicities reported during cycle 1 were: hypersensitivity (23% of pts), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis occurred in 3% and thrombosis in 3% of pts. One pt experienced a transient ischemic attack. The most common grade 3 or 4 adverse event was febrile neutropenia (7%). There were no deaths. Conclusions The majority (83%) of children and adolescents with ALL or LBL receiving Erwinia IV at 25,000 IU/m2/dose on a M/W/F schedule, achieved NSAA ≥0.1 IU/mL at 48 hrs postdose 5 (considered the therapeutic goal); however the majority did not achieve this goal at 72 hrs post Erwinia dose 6. With IV administration, asparaginase-related toxicities appeared to be consistent with previous reports in children treated with IM Erwinia. Based on these results, we are now evaluating IV Erwinia at 25,000 IU/m2/dose administered every 48 hrs rather than on a M/W/F schedule. This study was funded by Jazz Pharmaceuticals plc. Disclosures: Off Label Use: ERWINAZE (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL)who have developed hypersensitivity to E. coli-derived asparaginase. The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase. Hijiya:Jazz Pharmaceuticals: Consultancy. Brown:Jazz Pharmaceuticals: advisory board Other. Drachtman:Jazz Pharmaceuticals: Honoraria. Messinger:Jazz Pharmaceuticals: Advisory Board Other. Plourde:Jazz Pharmaqceuticals: Employee of Jazz Pharmaceuticals, Inc, who in the course of this emplyment has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc Other, Employment. Silverman:Enzon Pharmaceuticals: Consultancy; Sigma Tau Pharmaceuticals: Advisory Board, Advisory Board Other; EUSA Pharma: Advisory Board Other.

Abstract 882 Background: Nearly 20% of children with ALL relapse within 5y from diagnosis. Second-line therapies are toxic and salvage is poor. Systemic exposure to 6MP is critical for durable remissions; low systemic exposure due to nonadherence to oral 6MP could potentially increase relapse risk. We have previously reported on adherence to oral 6MP in non-Hispanic whites and Hispanics, (J Clin Oncol 2012;30:2094-101); this report extends follow-up for assessment of disease status by 68,250 person-days for non-Hispanic whites and Hispanics; it also includes adherence data for a previously unreported cohort of African American and Asian children. The goal of this report was to: i) describe adherence to oral 6MP in a multi-ethnic cohort of children with ALL; ii) identify determinants of adherence; iii) describe impact of adherence on relapse; and iv) define a clinically-relevant level of adherence needed to minimize relapse risk. Methods: Microprocessor chips in Medication Event Monitoring System (MEMS) caps recorded date/time of 6MP bottle openings for 6 mos/ patient. Adherence rate was defined as days of 6MP bottle opening, divided by days of prescribed 6MP (removing days when 6MP was withheld for toxicity/illness from denominator). Monthly red cell thioguanine nucleotide (TGN) levels were used to demonstrate that MEMS bottle openings were accompanied by 6MP ingestion. Analyses used Generalized Estimating Equations. Results: 462 patients (168 Hispanics; 157 non-Hispanic whites; 69 Asians; 68 African Americans) yielded 76,055 person-days of adherence data. Median age at participation was 6y (2-20); 67% were males; 40% had high-risk disease per NCI criteria; 61% reported income Conclusions: Non-adherence to 6MP is prevalent in children with ALL; 45% consume Disclosures: Relling: St. Jude Children's Research Hospital: Dr. Mary Relling receives a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms and GGH polymorphisms. Dr. Mary Relling receives a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms and GGH polymorphisms. Patents & Royalties; Sigma-Tau Pharmaceuticals: Research Funding.

Abstract 2509 Background: Chronic pediatric immune thrombocytopenia (ITP) has an incidence of 1–2/100,000. Due to its low incidence, large studies in pediatric chronic ITP are difficult. This registry includes patients from 16 sites in the US and Canada and represents one of the largest longitudinal datasets of children/adolescents with chronic ITP. Objective: To describe the North American Chronic ITP Registry (NACIR) study population and evaluate univariate predictors of platelet count response to therapies, including IVIG, anti-D globulin (anti-D), steroids (5–14 day course), and splenectomy. Registry methods and patient characteristics: After local IRB approval, 550 patients with chronic ITP enrolled in the NACIR between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 7 days of IVIG, 10 days of anti-D, 14 days of steroids, and 30 days of splenectomy. 365 subjects had at least one 6 month follow-up report after enrollment; median duration of follow-up was 2.1 yrs. Demographics of participants include: 46% male; 84% Caucasian, 7% Black, and 7% Asian; and 20% Hispanic. Mean age at diagnosis of acute ITP was 8.7 ± SD 5.2 years. At the time of enrollment in NACIR, subjects had received a median of 2 prior treatments (range 0–7). Results: The median platelet count at diagnosis of acute ITP was 11,000/uL (IQR 6,000–31,000/uL) and at chronic ITP was 35,000/uL (IQR 18,000–66,000/uL). 69 (12.5%) patients had secondary ITP or Evans syndrome. Of those tested, 25.6% (98/359) of patients had a positive ANA (titer > 1:40), and 75/337 (22.3%) had a positive direct anti-globulin test (DAT). 27.5% of patients had an antecedent viral illness. Of the 550 subjects, 2 (0.4%) experienced life-threatening bleeding. Patients were treated as follows: 259 (47.1%) with steroids, 253 (46%) with IVIG, 189 (34.4%) with anti-D, and 64 (11.6%) with splenectomy. Overall responses to therapy included: 69.1% response to steroids, 74.3% response to IVIG, 66.7% response to anti-D, and 85.9% response to splenectomy. Univariate predictors of response to treatments are shown in Table I. Higher platelet count at chronic ITP diagnosis and DAT positive predicted a platelet response to a short course of steroids in univariate analysis. This was confirmed in multivariable analysis of potential confounders, using logistic regression with a backwards elimination procedure. Response to one type of therapy was often strongly associated with a response to a second therapy. Gender, ethnicity, race, older age, and platelets ≥20,000/uL at acute ITP diagnosis were not associated with response to any single therapy. Conclusion: The demographics and laboratory findings of the large, well characterized NACIR population are consistent with other reports of young people with chronic ITP. The novel finding that DAT positivity predicts steroid response, even with multivariable adjustment for confounders, provides evidence that the NACIR is a robust and useful tool for trying to predict response to ITP treatment strategies. Disclosures: Klaassen: Novartis: Research Funding; Cangene: Research Funding. Lambert: Cangene: Membership on an entity's Board of Directors or advisory committees.

9512 Background: Anthracycline-related cardiomyopathy is a well-recognized dose-limiting complication. Inter-individual variability in risk exists, potentially due to genetic susceptibility. Carbon...

BACKGROUND: Obtaining laboratory studies to screen for a coagulation disorder prior to tonsillectomy and/or adenoidectomy (T&A) is a controversial procedure. The American Society of Pediatric Otolaryngology advises that such studies only be performed when indicated by history or physical exam. Nevertheless, many surgeons in clinical practice proceed with testing on all children scheduled for T&A. Several observational studies of pre-operative testing have been performed over the past four decades with conflicting results. The cost-effectiveness of this screening has not been studied in a rigorous, formal manner. We constructed a decision analysis model to address the costs and health outcome states of coagulation screening strategies for children undergoing T&A. METHODS: A 14-day Markov model was constructed to test three pre-operative screening strategies: test all children for coagulation disorders; test only those children with a pertinent history or physical exam (PE) finding; and perform no pre-operative testing on any child. We performed a literature search to estimate the prevalence of abnormal pre-operative coagulation tests, the prevalence of true coagulation disorders among those patients, the rates of bleeding following T&A, and the mortality following T&A. From published sources, we obtained cost data on laboratory studies, hospital admissions (surgical and observational), hematology consultation, medications for prophylaxis and treatment of a bleeding disorder, and lost parental wages. We estimated quality of life (utility) data from published national sources. Parameters were varied widely in sensitivity analyses based upon the range of reported values. Using a societal perspective and a cycle length of one day, we compared the three strategies based on total costs and quality-adjusted life-years (QALYs). RESULTS: Total costs for the three strategies were $3200 for testing all children, $3083 for testing only children with a history or PE finding, and $3077 for not testing children. Total utilities followed a reversed pattern with 0.02579 QALYs for testing all, 0.02654 QALYs for testing some, and 0.02659 QALYs for not testing. These results indicate that the strategy of not testing children prior to surgery dominates the others; it is both less expensive and has a higher utility. Cost-effectiveness ratios were sensitive to variation in the overall prevalence of post-operative bleeding, the cost of post-operative care, and the cost of diagnostic coagulation testing after a post-operative hemorrhage. However, the strategy of not testing children pre-operatively was dominant throughout all sensitivity analyses. DISCUSSION: Our results demonstrate that universally screening all children for coagulation disorders prior to T&A is not cost-effective. Furthermore, not performing any preoperative testing appears to be the most cost-effective strategy. This study does not prove the superiority of one strategy over another, though it does offer advantages over single institution observational studies. Given the short time duration of the model, absolute cost and utility differences between strategies are small. However, these differences are persistent in sensitivity analyses, indicating that the model is robust. The analysis provides evidence that suggests pre-T&A coagulation testing in children should be used judiciously at most. Detailed conversations between surgeon, patient, and family about the risks, benefits, and costs of such testing should determine its selective use.

Background & Aim: The current recommended starting dose of enoxaparin in children is 1 mg/kg/dose administered twice-daily. Studies in adults, however, have demonstrated similar safety and efficacy between once-daily enoxaparin (1.5 mg/kg/dose) and twice-daily (1 mg/kg/dose) in the initial and long-term treatment of venous thromboembolism. Due to known differences in heparin clearance between adults and young children, recommendations for once-daily enoxaparin dosing should not simply be extrapolated from adult literature. Our objective was to perform a pilot study to describe the pharmacodynamics of once-daily enoxaparin in children, and to gather preliminary data regarding safety and feasibility. Methods: 15 patients, ages 3 months to 16 years, with newly diagnosed thromboembolism were enrolled. All began therapy with 1.5 mg/kg enoxaparin administered once-daily. Initial peak anti-Xa levels were drawn 4–6 hours after the second dose of enoxaparin. Dose adjustments were made according to a study nomogram to achieve peak anti-Xa levels between 1–2 U/ml, as recommended by the American College of Pathologists for once-daily enoxaparin dosing. Once therapeutic levels were achieved, a subgroup of 8 patients underwent 24–hour pharmacodynamic (PD) monitoring, with anti-Xa levels drawn at Hours 0, 2, 4, 8, 12, 18, and 24. Results: 14 patients completed the study. 8 of 14 children required a final dose of >2 mg/kg to achieve target peak anti-Xa levels (Table). Only one participant (age 15 years) achieved target levels with the original dose. In PD studies, 7 of 8 children had subtherapeutic anti-Xa levels by Hour 12, and 4 of 8 had unmeasurable levels by Hour 18 (Figure). These results differ from adult studies in which therapeutic levels (0.5–1.0 U/ml) have been measurable 13–18 hours after administration, and prophylactic levels (0.1–0.3 U/ml) have been measurable at 24 hours. There were no new or recurrent thrombotic events. One patient was removed from the study on Day 2 because anticoagulation was permanently discontinued after a post-surgical bleed (anti-Xa 0.23 at time of event). Conclusion: Our pilot data suggests faster clearance of once-daily enoxaparin in the pediatric population as compared to adults. The appropriate starting dose of once-daily enoxaparin in young pediatric patients is likely higher than 1.5 mg/kg. Dose adjustments needed to achieve target peak anti-Xa activity (1–2 IU/ml) Patient Age Weight (kg) Indication for enoxaparin Dose changes Final dose (mg/kg) DVT, deep venous thrombosis; CVL, central venous line 1 3 months 6.5 DVT with CVL 4 3.8 2 10 months 10 DVT with CVL 4 4 3 14 months 13 DVT with CVL 2 2.3 4 2 years 14 DVT with CVL 4 2.7 5 3 years 14 DVT 2 2.7 6 8 years 83 DVT with CVL 1 1.7 7 9 years 37 Arterial ischemic stroke 1 1.9 8 13 years 67 DVT with CVL 2 2.1 9 14 years 65 DVT with CVL 2 2.2 10 14 years 68 DVT 1 1.8 11 15 years 60 DVT with CVL 1 1.9 12 15 years 60 Arterial ischemic stroke 1 1.6 13 15 years 77 DVT with CVL 0 1.5 14 16 years 45 DVT 3 2.9 Figure Figure

There appears to be variability in both recommendations and practice regarding the route of administration of immunizations to infants and children with hemophilia. The CDC Advisory Committee on Immunizations, the American Academy of Pediatrics Red Book, and the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation all recommend intramuscular vaccination; the risk of bleeding can be minimized by concomitant administration of antihemophilic factor. However, informal discussions among practicing hematologists suggest that common practice is subcutaneous administration. METHODS: To determine the standard practice regarding immunizations a survey was completed by 12 Hemophilia Treatment Centers in Federal Region III (Mid-Atlantic states). The number of pediatric patients followed in each institution ranged from 9 to 182 (average 73). RESULTS: All centers have a policy or standard practice regarding the administration of vaccines and 10 of 12 recommend subcutaneous administration of all vaccines. Of the two centers that recommend following manufacturer guidelines one does and one does not routinely recommend concomitant factor administration. One center, whose policy is subcutaneous administration, recommends simultaneous factor administration if the primary care provider insists on intramuscular administration. Half of the centers do not offer immunizations on site; those that do usually offer only hepatitis A and B vaccines. All but one center have seen hematoma formation following immunizations, but none have seen sterile abscesses, necrosis, or granuloma formation. Hematomas have been seen following both subcutaneous and intramuscular injection. Estimates of hematoma formation are difficult to calculate, but one large program (folowing 182 patients) sees about 1 hematoma per year or an estimated 2–5% incidence. CONCLUSION: Contrary to CDC and MASAC guidelines, it is standard practice at most Hemophilia Treatment Centers in Federal Region III to recommend subcutaneous administration of all vaccines without coverage of factor replacement. Hematoma formation is uncommon and can be seen following either subcutaneous or intramuscular administration. There appears to be little indication for prophylactic factor treatment before vaccine administration.

A 2-year-old boy presented with sexual precocity secondary to a hormone-producing hepatoblastoma. The tumor demonstrated an aggressive histologic pattern and stained immunohistochemically for alpha-fetoprotein and beta-subunit human chorionic gonadotrophin. After a successful liver transplant these tumor markers were closely followed. We conclude that histologic subclassification of hepatoblastoma is most useful for predicting likelihood of resectability. Tumors with predominantly fetal-type histology tend to be better circumscribed and are more likely to be resectable with improved survival relative to tumors with predominantly embryonal histology. The presence or absence of mesenchymal elements does not seem to have prognostic importance. Anaplastic features predict a poor outcome, but it remains for these to be uniformly defined and applied. Small uniform cellular histology with neuroblastoma-like differentiation appears to be particularly ominous. Serologic tumor markers, especially alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) are useful as monitors of potential tumor recurrence, but their efficacy is compromised by the unpredictable variation of tumor cell metabolism, undoubtedly a result of the genetic instability and heterogeneity of proliferating malignant cells.

We investigated the effects of various steroids on erythroid colony formation by normal human bone marrow and peripheral blood, and by marrow and peripheral blood from 18 patients with primary hypoproliferative anemia. These agents were variously found to enhance both CFU-E and BFU-E derived colony growth by normal human cells. Fluoxymesterone and dexamethasone were the most active inducers of CFU-E proliferation, and etiocholanolone and dexamethasone were the most potent burst augmenters. Androsterone did not significantly influence BFU-E proliferation in 66% of the marrow cultures from hematologically normal donors. Colony formation by erythroid progenitor cells of the patients with hypoproliferative anemia was reduce (20 +/- 10 CFU-E derived colonies/6 X 10(4) marrow cells; 12 +/- 5 BFU-E derived colonies/1 X 10(5) blood cells) when compared to growth by normal cells (65 +/- 14 CFU-E derived colonies/6 X 10(4) marrow cells; 21 +/- 9 BFU-E derived colonies/1 X 10(5) blood cells). Colony formation by marrow or peripheral blood cells of eight patients with steroid-responsive anemia was only moderately reduced (26 +/- 11 CFU-E derived colonies/6 +/- 10(4) marrow cells; 17 +/- 3 BFU-E derived colonies/1 X 10(5) blood cells) when compared to growth by marrow cells of three steroid-unresponsive patients (3 +/- 1.5 CFU-E derived colonies/6 X 10(4) cells). Whereas the addition of steroids of the same class to marrow and peripheral blood cultures of the steroid-responsive patients enhanced colony growth by 60-300%, their addition to marrow cultures of the steroid-unresponsive patients increased colony growth by less than 60%. It appears that further investigations using in vitro culture techniques as predictors of response to steroid therapy in patients with hypoproliferative anemia may be warranted.

Patients with type I diabetes mellitus treated with continuous sc insulin infusion (CSII) have improved glucose homeostasis, metabolic control, and linear growth. To determine the influence of CSII on cellular growth in vitro, we used a clonal stem cell assay for proliferation of erythroid progenitors, [burstforming units-erythroid (BFU-E)] in peripheral blood. Eight patients were studied before and after 1 week of CSII. Improvement in metabolic control was demonstrated by a decrease in mean 24-h plasma glucose from 232 +/- 29 (+/- SEM) mg/dl before treatment to 112 +/- 3 mg/dl after treatment (P = 0.01). Somatomedin-C levels increased from 1.1 +/- 0.4 to 1.4 +/- 0.4 U/ml (P less than 0.001). Numbers of BFU-E-derived colonies were not different from normal during conventional treatment, but increased 300% after 1 week of CSII. Our findings indicate that the acute metabolic and hormonal improvements that accompany short term CSII therapy in vivo are associated with a striking increase in the proliferation of erythroid committed stem cells in vitro.

Etude pilote sur 21 enfants de 6 mois a 13 ans atteints de purpura thrombopenique idiopathique (PTI) avec un taux de plaquettes inferieur a 20000/μl, traites par 3 doses de 30 mg/kg de methylprednisolone. Resultat efficace sur les plaquettes, peu couteux, peu toxique, a comparer prospectivement avec les gamma-globulaires et les steroides oraux

Beta-thalassemia trait is a frequent cause of microcytic anemia in Mediterranean children. Because striking age-related changes occur in hemoglobin and mean corpuscular volume during childhood, we assessed developmental hematologic characteristics of 132 patients less than or equal to 18 years of age with beta-thalassemia trait. Thirty-nine kindred were studied to examine intrafamilial correlations of hematologic abnormalities. Patients with beta-thalassemia trait demonstrated Hgb values about 2 gm/dl below normal standards, with a progressive rise with age paralleling normal trends. Thalassemic MCV values showed a far greater deviation from normal than Hgb levels. In contrast to normal developmental trends which show a sharp increase in the first five years of life, the MCV in thalassemia trait showed no age-related increase prior to adolescence. No age-related changes in hemoglobin A2 levels were noted. Kindred studies demonstrate a correlation of the degree of anemia, microcytosis, and elevated hemoglobin A2 levels in affected family members (r = 0.318 P0.004, r = 0.525 P0.001, r = 0.416 P0.0015, respectively). Our findings support the use of electronically determined MCV values as an initial screening procedure for children with beta-thalassemia trait. Values of70 fl prior to adolescence and75 fl during adolescence were present in nearly all thalassemic subjects. Intrafamilial correlations of Hgb, MCV, and hemoglobin A2 levels suggest that these characteristics are genetically determined.

Summary To investigate the pathogenesis of polycythaemia in a child with isolated, primary erythrocytosis, we measured serum erythropoietin activity and in vitro erythroid progenitor cell responsiveness to erythropoietin. Unstimulated erythropoietin activity was markedly elevated (1.8 IU/ml), and isovolaemic phlebotomy induced a four-fold increment above this level. In contrast to findings in our index case with this syndrome, normal erythroid colony growth patterns were present in patient marrow cultures. The primary mechanism of polycythaemia in this individual is similar to that reported in the index case: an inappropriately elevated regulatory set point for erythropoietin production. Since an additional defect of progenitor cell hypersensitivity to erythropoietin is not always present, we conclude that abnormalities at single or multiple sites of the erythropoietic regulatory axis may occur in primary erythropoietin-dependent erythrocytosis.

The requirement of erythropoiesis for erythropoietin were studied in a patient with Ph chronic myelocytic leukemia who had undergone an erythroblastic transformation. Transfusions resulted in a suppression of erythropoiesis. Plasma clot culture studies indicated that both the CFU-E and BFU-E in the peripheral blood of this patient were dependent upon erythropoietin for their differentiation and proliferation. Neither of these committed erythroid stem cells was cloned in the absence of erythropoietin. These studies suggest that the proliferation and differentiation of erythroid stem cells during the erythroblastic crisis of this disorder remain dependent upon physiologic regulators.

Bacterial septicemia and meningitis are major causes of death in young children with sickle cell anemia. We report a prospective study of 182 episodes of fever among 22 children with sickle cell diseases identified at birth. The majority of patients with fever exceeding 39.5 degrees C were treated with antibiotics intravenously until results of blood cultures were known. Infectious diseases were documented in 38% of all febrile events. Six episodes of bacterial septicemia, two associated with meningitis, were successfully treated with no mortality or residual morbidity. These data form the basis of suggestions for management of the young child with sickle cell disease and fever.

The Cooperative Study of Sickle Cell Disease (CSSCD) is a multiinstitutional investigation of the natural history of clinical course of sickle cell disease from birth through adulthood. The study is not a trial; rather, it involves data collection at 23 institutions in a uniform, standardized fashion on 3800 patients. Recruitment aspects that were addressed include issues related to recruitment of different age groups, ranging from newborns to pregnant women to patients over 50 years of age; the need to include mildly affected patients to ensure that the study would not reflect only a severe hospital-based population; recruitment from rural populations; and the need to screen and enter a newborn population at birth. The recruitment goal of entering 3200 patients, including 2100 patients with SS hemoglobinopathy, over a 24-month period was accomplished after 27 months.

• We treated two children with sickle cell disease and intracranial hemorrhage. The incidence of intracranial hemorrhage is increased in sickle cell disease, although not as markedly as that of cerebral infarction. Intracranial hemorrhage has a higher mortality, a lower rate of permanent neurologic impairment, and occurs more often in older patients than does cerebral infarction. Intracranial hemorrhage in adults is likely to be an intracerebral hemorrhage or a subarachnoid hemorrhage secondary to an aneurysm. Children, however, are more likely to have subarachnoid hemorrhage without an identifiable aneurysm. We hypothesize that both hemorrhages and infarcts are due to large-vessel cerebral vasculopathy secondary to the abnormal rheologic features of sickled cells. ( AJDC 1985;139:1120-1123)

We have studied mechanisms causing reduced g mRNA accumulation in β-thal. One patient was studied by recombinant DNA cloning, nucleotide sequencing and in vitro functional analysis of the β-thal gene, and five others, by analysis of newly synthesized mRNA after pulse-chase labeling of erythroblasts with 3H-uridine. The cloned β-thal gene exhibited normal transcription in a cell-free system. The only nucleotide sequence abnormality occurs within the small intervening sequence (intron) and creates a potential anomalous splicing site in the mRNA precursor, suggesting a structural basis for defective processing. In four additional patients, defective β mRNA processing was also observed. The initial β/α 3H mRNA ratios of pulse-labeled RNA were normal, indicating normal transcription, but abnormally high accumulation of unprocessed β mRNA precursur sequences (introns) occurred in each case. A fifth patient exhibited normal 3H β mRNA synthesis and processing in nuclear RNA, but β mRNA in cytoplasm declined to steady-state levels during a 20-hour “chase,” indicating cytoplasmic instability. These studies identify at least two distinct post-transcriptional lesions in β mRNA metabolism in β-thal: inefficient processing of introns and cytoplasmic instability of mature β mRNA.

Children with sickle cell anemia have an increased susceptibility to bacterial infections, especially to those caused by Streptococcus pneumoniae. We therefore conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial to test whether the regular, daily administration of oral penicillin would reduce the incidence of documented septicemia due to S pneumoniae in children with sickle cell anemia who were younger than 3 years of age at the time of entry. The children were randomly assigned to receive either 125 mg of penicillin potassium (105 children) or placebo (110 children) twice daily. The trial was terminated 8 months early, after an average of 15 months of follow-up, when an 84% reduction in the incidence of infection was observed in the group treated with penicillin, as compared with the group given placebo (13 of 110 patients v 2 of 105; P = .0025). There were no deaths from pneumococcal septicemia in the penicillin-treated group but three deaths from the infection occurred in the placebo group. On the basis of these results, we conclude that children should be screened in the neonatal period for sickle cell hemoglobinopathy and that those with sickle cell anemia should receive prophylactic therapy with oral penicillin by 4 months of age to decrease the morbidity and mortality [SEE FIGURE IN SOURCE PDF.] associated with pneumococcal septicemia. (Previously published in N Engl J Med 1986;314:1593-1599.

Serum IgG inhibitors of erythropoiesis have been found in adults with acquired pure red cell aplasia but have not been described in children. We studied the mechanism of action of such an inhibitor in a 51/2 year old male with acquired erythroblastopenia and severe anemia of 4 months duration. After an unsuccessful trial of corticosteroids, normal erythropoiesis was established with the administration of Cytoxan(CT). When the patient's erythroblastopenic marrow cells were cultured in plasma clots, increased numbers of CFU-E and BFU-E derived colonies formed in the presence of erythropoietin. Addition of the patient's pretreatment whole serum both to erythroblastopenic autologous marrow and to allogenic normal marrow cells suppressed CFU-E but not BFU-E derived colony formation. The specific inhibitor of CFU-E derived colony formation was present in the IgG fraction of the pretreatment serum. Whole serum obtained following the CT-induced remission no longer inhibited erythroid colony formation. Acquired pure red cell aplasia associated with a serum inhibitor occurs in the pediatric age group. Our findings suggest that this inhibitor is an IgG immunoglobulin which acts directly on the more mature CFU-E but not on the less differentiated BFU-E precursor.

934 THE TWO-HOUR SICKLE CELL PREP (SCP) FOR RAPID DETERMINATION OF SICKLE HEMOGLOBIN (HB S)

To explore the nature of the defect in TEC, we utilized the plasma clot culture technique to study the effect of patients' serum on the proliferation of erythroid stem cells in vitro. Six patients with TEC, ages 1-4 yr., presented with an average hemoglobin of 6.2gm/dl and reticulocytopenia. Bone marrow (BM) aspiration revealed decreased or absent erythroblasts. Recovery was evident by 2 weeks in all patients. When 6x104 BM mononuclear cells obtained from 4 patients at the time of diagnosis were plated with 2 I.U. of erythropoietin, 1 patient had increased numbers (159) of CFU-E-derived colonies, 2 had decreased numbers (2;18), and in 1 patient there was none (Nl:58±6). Addition of 10% patient's serum to this syngeneic system resulted in 100% inhibition of erythroid colony formation in the patient with increased numbers of CFU-E, no effect on those with decreased colonies, and increased colony formation in the patient with absent CFU-E's compared to controls. When serum from the 2 other patients was added to allogeneic BM cells in culture, there was 58 and 81% inhibition of CFU-E-derived colony formation compared to controls. Study of recovery serum from the 3 patients with inhibitors revealed loss of inhibitory activity. We conclude that while TEC has a uniform clinical presentation, there are at least two pathogenetic mechanisms:(l)a serum inhibitor directed against erythroid stem cells and (2)an abnormality of erythroid stem cells either in number or in responsiveness to erythropoietin.