ALBERT

Description: In children with acute lymphoblastic leukemia (ALL), response to treatment is assessed by bone marrow aspiration. We investigated whether minimal residual disease (MRD) can be effectively monitored in peripheral blood. We used flow cytometric techniques capable of detecting 1 leukemic cell among 10 000 or more normal cells to compare MRD measurements in 718 pairs of bone marrow and peripheral blood samples collected from 226 children during treatment for newly diagnosed ALL. MRD was detected in marrow and blood in 72 pairs and in marrow but not in blood in 67 pairs; it was undetectable in the remaining 579 pairs. Remarkably, findings in marrow and blood were completely concordant in the 150 paired samples from patients with T-lineage ALL: for each of the 35 positive marrow samples, the corresponding blood sample was positive. In B-lineage ALL, however, only 37 of 104 positive marrow samples had a corresponding positive blood sample. Notably, peripheral blood MRD in these patients was associated with a very high risk for disease recurrence. The 4-year cumulative incidence of relapse in patients with B-lineage ALL was 80.0% ± 24.9% for those who had peripheral blood MRD at the end of remission induction therapy but only 13.3% ± 9.1% for those with MRD confined to the marrow (P = .007). These results indicate that peripheral blood may be used to monitor MRD in patients with T-lineage ALL and that peripheral blood MRD may provide strong prognostic information in patients with B-lineage ALL.

Description: There is conflicting information about the influence of body mass index (BMI) on the pharmacokinetics, toxicity, and outcome of chemotherapy. We compared pharmacokinetics, outcome, and toxicity data across 4 BMI groups (underweight, BMI ≤ 10th percentile; normal; at risk of overweight, BMI ≥ 85th and 〈 95th percentile; overweight, BMI ≥ 95th percentile) in 621 children with acute lymphoblastic leukemia (ALL) treated on 4 consecutive St Jude Total Therapy studies. Chemotherapy doses were not adjusted to ideal BMI. Estimates of overall survival (86.1% ± 3.4%, 86.0% ± 1.7%, 85.9% ± 4.3%, and 78.2% ± 5.5%, respectively; P = .533), event-free survival (76.2% ± 4.2%, 78.7% ± 2.1%, 73.4% ± 5.5%, and 72.7% ± 5.9%, respectively; P = .722), and cumulative incidence of relapse (16.0% ± 3.7%, 14.4% ± 1.8%, 20.6% ± 5.1%, and 16.7% ± 5.1%, respectively; P = .862) did not differ across the 4 groups. In addition, the intracellular levels of thioguanine nucleotides and methotrexate polyglutamates did not differ between the 4 BMI groups (P = .73 and P = .74, respectively). The 4 groups also did not differ in the overall incidence of grade 3 or 4 toxicity during the induction or postinduction periods. Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P 〉 .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL.

Description: Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n = 13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n = 2) or 0.2 mg/kg per day (n = 4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non–dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 μM (0.11-0.37 μM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 μM; area under the concentration times time curve (AUC0-24) was 2.50 μM-hr (1.28-3.85 μM-hr) and 4.37 μM-hr and 4.69 μM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.

Description: PURPOSE: To report a single institutional experience with presenting features, therapeutic approach and outcomes in pediatric mixed lineage acute leukemias, as defined by the WHO classification (including biphenotypic, bilineal and poorly differentiated leukemias). PATIENTS AND METHODS: Retrospective study of all pediatric patients with acute leukemias fulfilling the EGIL/WHO criteria for mixed-lineage leukemia, treated at St. Jude Children’s Research Hospital from 1985–2006. Features analyzed included morphology, cytochemistry, immunophenotype (flow cytometry), cytogenetics, therapy, response to therapy (including minimal residual disease level as detected by flow cytometry) and outcome. RESULTS: Of 1500 patients with newly diagnosed acute leukemia, 35 (21 boys and 14 girls), were diagnosed to have mixed lineage leukemia. They ranged in age between 2 days and 19 years (median, 10 years) and had a median leukocyte count of 18 × 109/L (range, 1 to 150 × 109/L). Morphologic and flow cytometric studies identified these leukemias as biphenotypic T-lymphoid/myeloid (20 cases), B-lymphoid/myeloid (10 cases), B/T-lymphoid/myeloid (2 cases), bilineal (2 cases) and undifferentiated (1 case). Sixteen cases showed cytochemical positivity for myeloperoxidase (1% to 90%, median 5%) and 9 cases had Auer rods. Twenty-three patients initially received standard induction therapy for AML (cytarabine, daunorubicin, and etoposide) and 12 patients received ALL-directed remission induction [prednisone, vincristine, L-asparaginase (PVA), and daunomycin]. Of the former group, 12 (52%) achieved complete remission (CR), 2 attained partial remission (PR), 8 had no response (NR), and 1 died of toxicity. Ten of the 12 patients (83%) who first received ALL therapy achieved CR and only 2 had NR. Thus, after initial induction therapy, 22 of the 35 patients (63%) achieved CR. However, 8 of the 10 patients who had NR or PR to AML therapy attained CR after receiving standard ALL induction therapy with only PVA, and 1 of 2 patients who had NR to ALL therapy achieved CR after receiving AML therapy, resulting in an overall CR rate of 91% (32 of 35 patients). Notably, of the 8 patients who did not respond to AML therapy but achieved CR after PVA, all 4 tested were MRD-negative after PVA and all 6 who received multiagent chemotherapy without transplantation are alive and in long-term remission for 1.1 to 16.4 years. Seven of these 8 patients had T-lymphoid/myeloid biphenotypic leukemia with expression of CD2, CD7, cytoplasmic CD3, and low MPO positivity (1% to 3.5%). Overall, among patients who achieved CR, 15 of 20 patients treated with chemotherapy alone are alive in remission, compared to only 4 of 11 patients who underwent transplantation. CONCLUSIONS: Pediatric patients with mixed lineage leukemia may benefit from a therapeutic approach directed against both AML and ALL. We suggest that patients who respond well to myeloid-directed therapy should continue to receive this therapy, whereas those who require lymphoid-directed induction should receive prolonged continuation treatment directed against both ALL and AML. Furthermore, our results indicate that patients with mixed lineage leukemias who achieve remission do not require stem cell transplantation to achieve long term survival.

Description: Age affects the treatment outcome in adults with acute myeloid leukemia (AML) but its effect in pediatric AML is less certain. We reviewed outcome in 423 patients, 21 years of age or younger, who were treated for newly diagnosed AML (excluding acute promyelocytic leukemia) at St. Jude Children’s Research Hospital (n=288) or M.D. Anderson Cancer Center (n=135) between 1983–2002. Patients were divided into those treated between 1983–1989 and 1990–2002. During these two time periods, distinct sets of protocols were used in both institutions, with higher intensity treatment used in the more recent era. After accounting for the effects of cytogenetics, Down syndrome (favorable), increased WBC (unfavorable), FAB type M7 (unfavorable) and early treatment era (unfavorable), every additional year of age conveyed a 4.4 % increase in the risk of death and a 3.3% increase in the risk of any adverse event (death, failure to achieve complete remission, or relapse), with p〈 0.001 for the effect of age on survival or event-free survival (EFS). When patients were divided into those above or below the median age (10 years), there was a significant interaction between age and treatment era (p=.05), with patients below 10 having better EFS when treated in the recent era. For patients below 10, the relative risk of an event was 1.6 folds higher in the early treatment era than in the recent era ( p=.016). For patients 10 and older, the improvement in EFS according to treatment era was not significant. Treatment site did not influence the EFS or survival, and the effects of age were similar at both sites. These results suggest that age is an independent prognostic factor in childhood AML with younger children benefiting from more intensive treatment than their older counterparts.

Description: Background: Clofarabine, a next generation nucleoside analogue, was well tolerated and demonstrated activity in adult and pediatric Phase I trials conducted in heavily pretreated leukemia patients. Multicenter Phase II studies in pediatric leukemia have completed accrual in the US and are reported here. Methods: Two Phase 2, multicenter, open-label studies were conducted with clofarabine in children with refractory or relapsed ALL or AML. Clofarabine was administered intravenously over 2 hours at 52 mg/m2/day for 5 consecutive days. Cycles were repeated every 2 to 6 weeks based on response and toxicity. Results: The studies enrolled 100 patients (60 ALL and 40 AML). Currently, data are available for 84 patients (49 ALL, 35 AML). Median age is 12 years (range 1 to 22 years) and median number of prior regimens is 3 (range 1 to 6). Thirty-nine percent had received prior bone marrow transplant (BMT). As determined by independent review, preliminary data indicate overall response rates of 31% in ALL (6 CR, 4 CRp, and 5 PR) and 26% in AML (1 CRp and 8 PR). Median duration of remission for ALL is 9.7 weeks (range 1.0 to 28.6) and for AML is 16.2 weeks (range 1.7 to 56.6+). Thirteen of 24 responding patients (54%) proceeded to BMT. Median survival was 42 weeks (range 7.0 to 63.1+) for responding ALL patients (CR+CRp+PR) and 39 weeks (range 7.7 to 93.6+) for responding AML patients (CRp+PR). Patients who failed treatment or were non-evaluable had shorter median survival; 7.4 weeks (range 0.9 to 40.1+) and 12.4 weeks (range 1.6 to 84.9+) for ALL and AML, respectively. Among the patients who were refractory to the last prior chemotherapy, 7/30 (23%) with ALL and 4/22 (18%) with AML achieved a response with clofarabine. Median duration of remission in these patients is 4.6 weeks (range 2.3 to 24.4+) for ALL and 20 weeks (range 1.7 to 56.6+) for AML. Most drug-related adverse events were transient including febrile neutropenia, diarrhea, nausea/vomiting, fever, skin rash, headache, elevation in liver enzymes and bilirubin, and infusion-related flushing and anxiety. Conclusions: Clofarabine is active as a single agent in pediatric ALL and AML that are refractory to intensive salvage regimens. The overall safety profile is similar to that reported in other pediatric salvage studies. Clofarabine in combination with standard chemotherapy is currently under investigation in children.

Description: Introduction After treatment response, cytogenetics and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about the impact of cytogenetics at relapse. This international retrospective study aimed to provide insight into the prognostic impact of cytogenetic profiles and the role of karyotype changes from diagnosis to relapse in pediatric patients with relapsed AML. Methods Cytogenetic reports from patients registered to the Relapsed AML 2001/01 Study and diagnosed between 2001 and 2010 were centrally reviewed and classified by two independent researchers plus a cytogenetic expert. Patients with refractory or relapsed AML and available cytogenetics at relapse were included in order to assess the prognostic impact of different cytogenetic subgroups at relapse. Patients with karyotypes available at both diagnosis and relapse were included in order to study the impact of karyotype changes. Recurrent cytogenetic aberrations present in ≥5 patients defined the subgroups. Changes at relapse were categorized as: no change, gain, loss, both gain and loss, or structural other aberration(s). Primary endpoints were the probabilities of event-free survival (pEFS) and overall survival (pOS). Univariate analyses were conducted using chi-square tests, binary univariate logistic regression or Kaplan Meier estimates with a log-rank test. Multivariable Cox regression analyses were conducted to evaluate the independent impact of cytogenetic profiles and karyotype changes at relapse. For these analyses, cytogenetic subgroups were regrouped into good risk (GR) cytogenetics [t(8;21)(q22;q22) or inv(16)/t(16;16)(p13.1;q22)] or "other". Results Of the 569 registered patients, 402 patients (71%) had available cytogenetic information at relapse. Frequently detected aberrations at relapse were t(8;21) (n=60, 15%) and inv(16)/t(16;16) (n=24, 6%), both indicating a relatively good prognosis. Although patient numbers were small (n=5), t(6;9)(p23;q34) also had a relatively good outcome. Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23) and complex karyotypes had a relatively poor outcome. Figure 1 shows the Kaplan Meier curves of the investigated cytogenetic subgroups with corresponding patient numbers. In total, 306 patients (54%) with available karyotypes at both diagnosis and relapse were included to study cytogenetic changes. Patients with any change (n=148, 48%) had inferior outcome compared to patients without changes (3-year pEFS 21% [SE, 3.4%] versus 39% [SE, 3.9%]; overall P

Description: To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%;P ≤ .038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%;P = .019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%;P = .019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P 

Description: Abstract 3604 Background: Clofarabine is a nucleoside analog that potently inhibits ribonucleotide reductase and DNA polymerase α. The biochemical modulation of cytarabine by clofarabine via inhibition of ribonucleotide reductase is well established, and this combination has been studied in adults with relapsed AML1, 2. We have previously reported the toxicity profile of the Phase I portion of AAML05233. Here, we report the Phase II portion of AAML0523 in children with relapsed AML. Study Design: Clofarabine and cytarabine were administered on days 1–5. Cytarabine (1 gm/m2) was given 4 hours after the start of clofarabine to optimize the biochemical modulation of ara-CTP. Patients were encouraged to receive 2 cycles of induction therapy, based on previous trials demonstrating response after a second cycle in those without response after the first4. The Phase I portion of AAML0523 determined that clofarabine at a dose of 52 mg/m2/day can be given safely in combination with cytarabine3. Results: 47 eligible AML patients were enrolled at the dose of 52 mg/m2 of clofarabine. One patient did not have bone marrow evaluation after course 1 and therefore was not evaluable for response. The median age at study entry was 14.1, the median length of CR1 was 306 days (range 35–2212), 44 patients were in first relapse, and 3 were primary refractory. Only 4 had prior stem cell transplant. The most common toxicities grade 3 or higher were: febrile neutropenia (36%), diarrhea (12%), nausea (11%), infection (51%), and hypokalemia (24 %). Four patients had capillary leak syndrome after the first cycle. There were no treatment-related deaths in AML patients. Response was measured as best response after up to 2 cycles of Induction. Of the 46 patients evaluable for response, 16 (35%) had complete response (CR), 5 (11%) CR with incomplete platelet recovery (CRp), 14 stable disease (SD), and 11 had progressive disease (PD). Of the 21 responders, 11 had SD after induction course 1 but then achieved CR or CRp after course 2. However, 8 non-responders who achieved SD after course 1 were then taken off study, mostly at physician's discretion to pursue other therapy. Four patients met conventional criteria for CRi (complete response with incomplete count recovery) and then received stem cell transplant, but this was not included among the study response definitions. Among all responders, median time to relapse was 374.5 days (range 42–2212), 16 went on to HSCT, and 3-year overall survival was 51±34%. Conclusions: The overall response rate (ORR) of 46 % (21 patients) did not meet the statistical threshold for efficacy of 50% (23 patients) developed for this study. Factors involving study compliance (8 SD patients did not receive course 2; 4 CRi patients did not await count recovery) may have affected the ORR. However, this non-anthracycline salvage regimen may be effective as a bridge to potentially curative HSCT in this high risk patient population. Disclosures: Off Label Use: Clofarabine is approved for use in ALL in second relapse. This presentation will discuss a clinical trial using clofarabine for children with AML in first relapse.

Description: In a double-blind, placebo (PBO)-controlled study of children age 5–18 years (y) with cancer and anemia who received myelosuppressive chemotherapy (CT), the use of epoetin alfa (EPO) increased hemoglobin (Hb) levels (Hb increase ≥1 g/dL from baseline after 4 weeks [wks], independent of RBC transfusion in the previous 28 days; 65.0% for EPO vs 50.0% for PBO; P=.034) and reduced transfusion requirements (transfusion after wk 4 = 51.4% for EPO vs 69.4% for PBO; P=.008). However, no difference in the primary end point, self-reported quality of life (QOL) using the Pediatric Quality of Life Inventory (PedsQL-I™), was observed overall between the 2 treatment arms (ProcASCO 23:abstract 8527, 2004). In adults, increases in Hb during EPO therapy are associated with improved QOL (Cancer95:888, 2002). Given these findings, this post-hoc analysis of the pediatric study was undertaken to determine if a difference in QOL outcomes is observed when the Hb response of children is considered. The study included patients (pts) who were receiving myelosuppressive CT for malignant solid tumors (ST), Hodgkin’s disease (HD), acute lymphocytic leukemia (ALL), or non-Hodgkin’s lymphoma (NHL) and who were anemic (Hb 12 y, Hb 12 y, and Hb