Smita Bhatia, MD, MPH; Wendy Landier, PhD, RN; Lindsey Hageman, MPH; Yanjun Chen, MS; Heeyoung Kim, MPH; Can-Lan Sun, PhD; Nancy Kornegay, MS; William E. Evans, PharmD; Anne L. Angiolillo, MD; Bruce Bostrom, MD; Jacqueline Casillas, MD, MSHS; Glen Lew, MD; Kelly W. Maloney, MD; Leo Mascarenhas, MD, MS; A. Kim Ritchey, MD; Amanda M. Termuhlen, MD; William L. Carroll, MD; F. Lennie Wong, PhD; Mary V. Relling, PharmD

PURPOSE:To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification.PATIENTS AND METHODS:Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children’s Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three).RESULTS:There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07).CONCLUSION:GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

Several studies have shown comparable survival outcomes with different graft sources, but the relative resource needs of hematopoietic cell transplantation (HCT) by graft source have not been well studied. We compared total hospital length of stay in the first 100 days after HCT in 1577 patients with acute leukemia in remission who underwent HCT with an umbilical cord blood (UCB), matched unrelated donor (MUD), or mismatched unrelated donor (MMUD) graft between 2008 and 2011. To ensure a relatively homogenous study population, the analysis was limited to patients with acute myelogenous leukemia and acute lymphoblastic leukemia in first or second complete remission who underwent HCT in the United States. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation. For children who received myeloablative conditioning, the median time alive and out of the hospital in the first 100 days was 50 days for single UCB recipients, 54 days for double UCB recipients, and 60 days for MUD bone marrow (BM) recipients. In multivariate analysis, use of UCB was significantly associated with fewer days alive and out of the hospital compared with MUD BM. For adults who received myeloablative conditioning, the median time alive and out of the hospital in first 100 days was 52 days for single UCB recipients, 55 days for double UCB recipients, 69 days for MUD BM recipients, 75 days for MUD peripheral blood stem cell (PBSC) recipients, 63 days for MMUD BM recipients, and 67 days for MMUD PBSC recipients. In multivariate analysis, UCB and MMUD BM recipients had fewer days alive and out of the hospital compared with recipients of other graft sources. For adults who received a reduced-intensity preparative regimen, the median time alive and out of the hospital during the first 100 days was 65 days for single UCB recipients, 63 days for double UCB recipients, 79 days for MUD PBSC recipients, and 79 days for MMUD PBSC recipients. Similar to the other 2 groups, receipt of UCB was associated with a fewer days alive and out of the hospital. In conclusion, length of stay in the first 100 days post-transplantation varies by graft source and is longer for UCB HCT recipients. These data provide insight into the resource needs of patients who undergo HCT with these various graft sources.

This book is a comprehensive and up-to-date compendium on all aspects of blood and marrow transplantation in children. After an introductory chapter describing the history of pediatric blood and marro

High-dose therapy with AutoHCT is a standard component of therapy for many patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL). IPS is a known toxicity of AutoHCT which can cause significant morbidity and mortality. The most common agent associated with IPS has traditionally been high-dose BCNU (carmustine). Data on incidence of IPS in recent era and its relation with conditioning regimens are scarce.

Background. This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. Procedure. Patients with <400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with >= 400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B). Results. Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 +/- 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. Conclusion. Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value. (C) 2014 Wiley Periodicals, Inc.

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy‐eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease‐free survival (DFS) was 24% at a median of 3 years. Post‐transplant leukemic relapse was more frequent than expected for children with DS‐ALL (54%) than for non‐DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS‐ALL. Pediatr Blood Cancer 2014;61:1126–1128. © 2014 Wiley Periodicals, Inc.

It is important to keep in mind that preparative regimens in hematopoietic cell transplant (HCT) are typically disease specific and have undergone prospective investigation and validation in clinical trials before becoming widely used. Thus, the choice of a specific preparative regimen is usually the result of selecting from a series of regimens that have been shown to be effective for a given disease. Within the group of recommended regimens, consideration should be given to the status of the disease at time of the HCT (more intensive regimens are usually preferred for disease states with high relapse risk) and the patient’s overall health condition (less-intensive regimens are usually preferred for patients with comorbid conditions or to avoid late effects, like infertility). Novel preparative regimens are not recommended outside of a prospective clinical trial. Another important issue in pediatric HCT is that there have been few randomized trials comparing regimens to assess superiority.

![Graphic][1] Background Escalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic alternatives. Objective To determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML. Methods Patients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD). Results Between 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in [Table 1][2]. Median follow-up was 3.6 (range 0-6.4) years for those alive. View this table: Table 1 Characteristics of randomized patients Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age 100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). [Table 2][3] illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). [Table 1][2] shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, [Table 2][3] shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm. View this table: Table 2 Outcomes by randomized treatment assignment following CR Conclusion GO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission. Disclosures: No relevant conflicts of interest to declare. [1]: /embed/inline-graphic-2.gif [2]: #T1 [3]: #T2

Introduction Abnormalities of 12p are relatively rare in acute myeloid leukemia (AML), but are of particular interest because ETV6, an ETS family transcription factor that frequently acts as a tumor suppressor , maps to 12p13. In pediatric AML the recurrent t(7;12)(q36;p13) has been recognized in addition to other heterogeneous 12p abnormalities which results in the rearrangement or deletion of ETV6 . Recently, a Medical Research Council study found that AML patients with 12p abnormalities have a poor prognosis. To date, abnormalities of 12p have been categorized as standard cytogenetic risk in Children’s Oncology Group (COG) AML trials, but there are limited data on their frequency, morphologic classification, and concomitant gene mutations or chromosome abnormalities. Objective To evaluate characteristics and prognostic significance of 12p abnormalities in AML in the COG trial AAML0531. Methods AAML0531 is a recently completed COG trial that enrolled patients between 2006 and 2010. Central review of cytogenetics was conducted on 981 of 1070 enrolled patients (non-Down syndrome) with de novo AML. Abnormalities of 12p were classified into 3 groups: 1) the t(7;12) or variants thereof; 2) abnormalities of band 12p13 other than the t(7;12) that were confirmed or highly suggestive of ETV6 rearrangement (other ETV6R); and 3) abnormalities resulting in loss of the band 12p13 (ETV6Loss). The entire group of children with 12p abnormalities ( N =32) as well as the three subgroups were compared with children ( N =949) without 12p abnormalities, with respect to demographics, frequency of gene mutation, additional cytogenetic abnormalities and survival. Results Abnormalities of 12p were identified in 32 (3.3%) of patients. 8 patients had a t(7;12) after central review (6 were missed in the local laboratory’s initial submission); 10 had otherETV6R, and 14 had ETV6Loss. The median age of the 12p group was significantly lower (median, 5.8; range, 0.2–18.2) than the non-12p group (median, 9.9; range, 0.003–29.8; P =.018). Notable was the very young age of patients with the t(7;12) (median, 0.6; range, 0.2–6.4; P =.004), with 88% 6 abnormalities, compared to 0% in the other 12p groups and 4% in the non-12p groups ( P <.002). On the basis of karyotype classification strategy in AAML0531 no patient with 12p abnormalities was low risk, 29 were standard risk, and 3 were high risk [due to presence of -5/5q- or -7]. The 12p abnormality group had a worse 3-year OS (28±17% vs. 69±3%, P .1). Conclusions Patients with abnormalities of 12p should be considered for categorization as high-risk with respect to cytogenetic stratification for AML. Given the subtle nature of the t(7;12) and other ETV6 rearrangements and their prognostic implications FISH for ETV6 is recommended upfront for the evaluation of any young patient with AML with a +19 as a secondary abnormality and in any patient suggestive of 12p deletion or rearrangement. Disclosures: No relevant conflicts of interest to declare.

BackgroundA majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization.ProcedureA single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive.ResultsNine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response.ConclusionOxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA. Pediatr Blood Cancer 2014;61:11-19. (c) 2013 Wiley Periodicals, Inc.

Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.

Pediatric Blood & CancerVolume 60, Issue 6 p. 897-898 Editorial Commentary The American society of pediatric hematology/oncology (ASPHO) 2013 distinguished career award goes to Dr. Gregory H. Reaman Maura C. O'Leary MD, Corresponding Author Maura C. O'Leary MD Washington, District of ColumbiaW East 2510 Virginia Ave, NW Washington, DC 20037.===Search for more papers by this authorFranklin O. Smith MD, Franklin O. Smith MD Cancer Institute, University of Cincinnati, Cincinnati, OhioSearch for more papers by this authorNita L. Seibel MD, Nita L. Seibel MD Cancer Therapy Evaluation Program, Bethesda, MarylandSearch for more papers by this author Maura C. O'Leary MD, Corresponding Author Maura C. O'Leary MD Washington, District of ColumbiaW East 2510 Virginia Ave, NW Washington, DC 20037.===Search for more papers by this authorFranklin O. Smith MD, Franklin O. Smith MD Cancer Institute, University of Cincinnati, Cincinnati, OhioSearch for more papers by this authorNita L. Seibel MD, Nita L. Seibel MD Cancer Therapy Evaluation Program, Bethesda, MarylandSearch for more papers by this author First published: 28 March 2013 https://doi.org/10.1002/pbc.24528Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume60, Issue6June 2013Pages 897-898 RelatedInformation

BACKGROUND: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML. METHODS: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m 2 /dose was administered on Day 6 of Course 1 and Day 7 of Course 4. RESULTS: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 +/- 6% and 66 +/- 5%, respectively. CONCLUSIONS: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide. Cancer 2012; 118: 761-9. (C) 2011 American Cancer Society.