ALBERT

Description: In infant ALL a constellation of features (young age, hyperleukocytosis, extramedullary/CNS disease, CD10− phenotype, MLL translocation, slow early response to treatment) are associated with poor outcome. Despite the frequent MLL translocations, the biologic basis for these features is unknown. In this study, gene expression profiles of leukemia cells from diagnosis were determined in MLL-rearranged infant ALL and relationships were sought between gene expression and clinical covariates. Patients and Methods: Seventeen infants treated on COG protocol CCG 1953 were studied. Features at diagnosis were: age, 0–333 d, median 121 d; WBC count, 10.2–1,286 ×103/μL, median 229 ×103/μL; CD10−, 14, CD10+, 2, CD10 unknown, 1; CNS1 status, 11, CNS2 status, 2, CNS3 status, 4. Eight were alive and 9 were dead at survival times from 41–3384 d. MLL translocations were identified using karyotype, FISH, Southern blot and PCR. Gene expression profiling was performed with Affymetrix HG_U133 Plus2.0 arrays. Pearson’s correlation coefficients and significance levels were computed between age and log-2 transformed expression levels of each probeset. To find associations between gene expression and MLL partner genes with the age effect controlled, linear regression was run using gene expression as the dependent variable and age and partner gene (AF4 v. other) as the independent variable. Similar linear regressions were run for WBC count, CNS status (excluding CNS2) and survival status. Results: PCR identified the MLL partner genes AF4, ENL, AF9, AF10 and EPS15 in 6, 4, 2, 1 and 1 cases, respectively. In 1 case each with t(4;11)(q21;q23) or t(11;19)(q23;p13.3) partner genes were assigned based on karyotype. Another case harbored a t(6;9;11) (q21;p22;q23). Gene expression was affected more by age at diagnosis than any other factor. Remarkably, gene expression analysis by age at diagnosis as a continuous variable showed correlations of 2072 probesets, all but one of which were positive (p

Description: Severe aplastic anemia (SAA), an illness characterized by the depletion of hematopoietic precursors within bone marrow leading to pancytopenia, has an overall mortality rate of 〉75% if left untreated. For children with human leukocyte antigen (HLA)-identical sibling donors, the treatment of choice for acquired SAA is allogeneic bone marrow transplant (BMT) with long-term survival of 70%–85%. For the 80% of children who lack suitable bone marrow donors, the standard treatment is immunosuppression with anti-thymocyte globulin (ATG), cyclosporine A (CSA), and often hematopoietic growth factors. Large series utilizing this immunosuppressive therapy have demonstrated a complete response rate of 60%–80%. When a patient does not have an HLA-identical sibling and fails to respond to conventional immunosuppression, options for further treatment are limited. One option is to pursue a matched unrelated donor (MUD) BMT, but matched donors are not available for all patients and long-term survival ranges between 20%– 60%. Treatment with high-dose cyclophosphamide is another option for refractory SAA patients that appears promising but has not been extensively studied in children. In 1999, a group of pediatric hematology centers joined together to study the use of high-dose cyclophosphamide for the treatment of children with acquired SAA not eligible for BMT and refractory to immunosuppression (Pediatric Aplastic Anemia Cooperative Trial #2). The goals of this study were to determine the response rate and toxicity associated with high-dose cyclophosphamide in children with refractory SAA. Between 10/1/99 and 6/3/02, 6 patients from 6 different centers were enrolled and received 4 days of intravenous cyclophosphamide (45 mg/kg/day), MESNA, and GM-CSF (250 mcg/m2/day SC) post-cyclophosphamide. The patient population consisted of 4 males and 2 females ranging in age from 2 to 18 years. The interval between diagnosis of SAA and cyclophosphamide treatment ranged from 8 to 88 months. All had failed to respond to earlier treatment with ATG and CSA. Twelve months following cyclophosphamide, there was 1 complete response (transfusion independent and normal blood counts), 1 partial response (transfusion independent but with moderate pancytopenia), 2 infectious deaths without recovery of blood counts, and 1 failure to respond. One patient was removed from the study before response could be assessed. High-dose cyclophosphamide in this population was associated with significant toxicity as 2 patients developed disseminated fungal infections within 30 days of starting therapy leading to death at day 18 in one. Another patient experienced grade 3 gingivitis/stomatitis lasting about 30 days. In summary, high-dose cyclophosphamide can lead to marrow recovery in some children with refractory SAA but is associated with the potential for life-threatening infectious complications, especially with fungus.

Description: CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P17 years, Afro-American and Hispanic ethnicity, body mass index 95th percentile for age, absence of related marrow donor, WBC 〉 50,000/mm3, karyotype with −7/7q, −5/5q- or 〉 cytogenetic 5 abnormalities, FLT3/ITD, 〉15 % morphologic blasts on day 14 or 〉0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.