ALBERT

Description: Background: Hematological malignancy patients receiving chemotherapy and hematopoietic stem cell transplant (HSCT) recipients experience considerable treatment related toxicities. Radiographic findings during febrile episodes present a therapeutic dilemma. Little is known about the trade-offs between diagnostic yield and risks for different diagnostic approaches in the investigation of lung lesions, namely broncho-alveolar lavage (BAL) and lung biopsy. Objective: The primary objective of this review was to describe the diagnostic yield of BAL and lung biopsy in the evaluation of pulmonary lesions in patients with hematological malignancies and HSCT recipients. The secondary objectives were to describe the rate of complications and procedure-related mortality of BAL and lung biopsy. Methods: Electronic searches of Ovid Medline from 1980 to March 14, 2014, EMBASE from 1980 to 2014 week 10, and Cochrane Central Register of Controlled Trials until January 2014 were conducted. Studies were included if pediatric and/or adult patients had hematological malignancy or were HSCT recipients and if patients underwent BAL or lung biopsy for the evaluation of a pulmonary lesion. We limited studies to full-text articles published in the English language after 1980. Studies with lung procedures conducted for initial diagnosis of cancer, surveillance and evaluation for drug toxicity, studies reporting only patients with positive diagnostic tests and studies done to validate a diagnostic test were excluded. Studies exclusively focusing on Pneumocystis jiroveci pneumonia (PCP) were excluded. Two reviewers independently identified articles and abstracted all data. Agreement of study inclusion between the two reviewers was evaluated using the kappa statistic. Synthesis of proportions was conducted using RevMan. All analyses were conducted using the natural logarithm of the proportion as the outcome. All estimates are presented as the proportion with the 95% confidence interval (CI). Heterogeneity was described using the I2 value and heterogeneity between sub-groups was evaluated using the chi-square statistic. Results: 14,148 studies identified by the search strategy and 266 were retrieved for full evaluation; 61 studies of BAL and 29 of lung biopsy were included in the final meta-analysis. Agreement of study inclusion between the two reviewers was almost perfect with kappa statistic = 87.9% (95% CI 82.0 to 93.9%). The proportion of procedures leading to an infectious diagnosis was 0.50 (95% confidence interval (CI) 0.46-0.55; n=44) for BAL and was 0.34 (95% CI 0.28-0.41; n=28) for lung biopsy. The proportion of procedures leading to a non-infectious diagnosis was 0.07 (95% CI 0.05-0.10; n=36) for BAL and 0.43 (95% CI 0.35-0.52; n=27) for lung biopsy. Change in management occurred more often with lung biopsy (0.47, 95% CI 0.39 to 0.57; n=15) compared with BAL (0.31, 95% CI 0.24 to 0.39; n=20). Transthoracic lung biopsies (0.38, 95% CI 0.32 to 0.47; n=23) were more likely to yield an infectious diagnosis compared to transbronchial procedures (0.12, 95% CI 0.06 to 0.24; n=5; P=0.002) and associated with more complications as compared to transbronchial procedures (P=0.02). The proportion of procedures with complications was 0.06 (95% CI 0.04-0.10; n=28) for BAL and 0.13 (95% CI 0.09-0.19; n=21) for lung biopsy. Procedure-related mortality was 0.20% (5/2,447) for BAL and 0.85% (5/589) for lung biopsy. Conclusions: BAL may be the preferred diagnostic modality for the evaluation of potentially infectious pulmonary lesions among patients with hematological malignancies and HSCT recipients because of lower complication and mortality rates and similar yield. Guidelines to promote consistency in the approach to the evaluation of lung infiltrates may improve clinical care of patients. Disclosures No relevant conflicts of interest to declare.

Description: Key Points There is no difference in survival after BMT among children of different BMI.

Description: Treatment-related mortality (TRM) is important in acute lymphoblastic leukemia and acute myeloid leukemia (AML); however, little is known about how TRM is defined across trials. Two major problems are related to what constitutes treatment versus disease-related cause of death and to TRM attribution (for example, death because of infection or hemorrhage). To address the former, we conducted a systematic review of randomized therapeutic pediatric acute leukemia and adult/pediatric acute promyelocytic leukemia trials and any study type focused on TRM in pediatric acute leukemia. We described definitions used for TRM. Sixty-six studies were included. Few therapeutic pediatric acute lymphoblastic leukemia studies (2/32, 6.3%) provided definitions for TRM, whereas more therapeutic pediatric AML studies (6/9, 66.7%) provided definitions. There was great heterogeneity in TRM classification. The authors of most studies relied on deaths during induction or in remission to delineate whether a death was TRM. However, 44.4% of therapeutic AML studies used death within a specific time frame to delineate TRM. We suggest that a consistent approach to defining and determining attribution for TRM in acute leukemia is an important future goal. Harmonization of definitions across the age spectrum would allow comparisons between pediatric and adult studies.

Description: Abstract 1071 Background: Treatment of children with acute myeloid leukemia (AML) is associated with considerable toxicity. Children's Oncology Group (COG) AAML0531 trial adopted a modified AML Medical Research Council backbone and reviewed adverse event reports in real time to maximize accurate toxicity data. As of March 31, 2010, AAML0531 had randomized 968 patients with de novo AML to gemtuzumab ozogamicin (GMTZ) versus no GMTZ. Accurate description of toxicities with the backbone regimen as well as increment toxicities of new agents is important to optimize supportive care. Objectives were to describe hepatic, cardiac and infectious toxicities and duration of neutropenia in all patients, and to compare toxicities between treatment arms. Methods: AAML0531 included those ≥ 1 month to ≤ 30 years with de novo AML and used a 5 cycle chemotherapy regimen: Induction (Ind) I and II: cytarabine, daunorubicin, and etoposide (ADE 10+3+5 and 8+3+5); Intensification (Int) I: cytarabine and etoposide; Int II: mitoxantrone and high-dose cytarabine; and Int III: high-dose cytarabine and L'asparaginase. Subjects were randomized to receive or not receive GMTZ 3 mg/m2 during Ind I and Int II. Common Terminology Criteria for Adverse Events v3.0 toxicities were collected prospectively. Hepatic (ALT, bilirubin and veno-occlusive disease (VOD)), cardiac (left ventricular systolic dysfunction (LVSD)) and infection (sterile site bacterial and fungal) toxicities were targeted. All grades of cardiac and VOD toxicities were captured; all other severe (≥ grade 3) toxicities were recorded. Cumulative incidence (CI) of toxicities was calculated only during protocol chemotherapy. Duration of neutropenia was reported from beginning of cycle to absolute neutrophil recovery ≥ 500/uL for patients alive during the cycle. Results: Table describes the prevalence of severe (≥ grade 3) toxicities and illustrates that severe high ALT occurred in 3–10%, high bilirubin was less common and VOD was reported in ≤ 1% of cycles. Severe LVSD also was rare although compliance with suggested cardiac monitoring ranged from 50–80% per course of treatment. In terms of grade 1 or 2 LSVD there were no differences in any course except for Int II where grade 1 or 2 LVSD was higher with GMTZ (8.0% versus 2.4%; P

Description: Abstract 1478 Background: Current therapies for pediatric acute myeloid leukemia (AML) are intensive; infections are responsible for considerable morbidity and most non-relapse related mortality (NRM). Three supportive care strategies that have garnered much attention are prophylactic antibiotics, prophylactic granulocyte-colony stimulating factor (G-CSF) and hospitalization during profound neutropenia. The Children's Oncology Group (COG) trial AAML0531 was a phase 3 study that included children with de novo AML treated with intensive chemotherapy, and randomized them to standard chemotherapy ± gemtuzumab ozogamicin. We surveyed participating COG sites mid-way through the trial to measure the effect of institutional standards for antibiotic prophylaxis, G-CSF prophylaxis, and discharge policy on Induction I infection risk and NRM for children on study. Methods: AAML0531 used 5 courses of intensive chemotherapy with Induction I consisting of cytarabine 100 mg/m2/dose intravenous (IV) every 12 h on days 1–10; daunorubicin 50 mg/m2/dose IV on days 1,3 and 5; and etoposide 100 mg/m2/dose IV on days 1–5 (ADE 10+3+5). Infections were collected prospectively and monitored in real-time to optimize reporting accuracy. In this analysis, infectious events were limited to Induction I to reduce the chance that a patient's clinical course resulted in the patient receiving a supportive care practice different than the institutional standard. NRM was not limited to Induction I and NRM was defined as any induction death or deaths during intensification or within 30 days of being taken off study due to non-disease related causes. The survey included questions on institutional standards for antibacterial prophylaxis, antifungal prophylaxis, prophylactic G-CSF use and mandatory hospitalization until count recovery. Results: A total of 1024 patients were enrolled on AAML0531. The survey response rate from 216 COG sites was 180/216 (83.3%) and there were 897 non-Down syndrome patients treated at institutions responding to the survey. The use of any anti-bacterial prophylaxis was not associated with a reduction in sterile site bacterial infection and did not significantly alter the risk of Clostridium difficile or fungal infection. Penicillin or vancomycin prophylaxis was associated with an increased risk of any sterile site bacterial infection (odds ratio (OR) 1.96, 95% confidence interval (CI) 1.15 to 3.34; P=.014), Gram-negative infection specifically (OR 4.22, 95% CI 1.62 to 11.0; P=.003) and sterile site fungal infection (OR 3.67, 95% CI 1.31 to 10.3; P=.013). Anti-mold prophylaxis was associated with more sterile site bacterial infection (OR 1.87, 95% CI 1.06 to 3.29; P=.031) and a non-significant increase in Gram-negative infection (OR 2.95, 95% CI 0.97 to 8.95; P=.056). Anti-mold prophylaxis did not influence the rate of sterile site fungal infection. G-CSF prophylaxis and discharge policy did not impact on Induction I infections. None of these supportive care practices influenced NRM during induction or intensification. Conclusions: Penicillin or vancomycin prophylaxis was associated with more Gram-negative and fungal infections. These data do not support routine prophylaxis with these agents. Routine antibiotic prophylaxis, G-CSF prophylaxis, and discharge policy did not impact NRM. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3223 Background: Delays in treatment are common in pediatric ALL and may occur more often in high risk ALL (HR-ALL). Delays during maintenance therapy have adverse impact on survival, but the significance of delays prior to maintenance is unknown (Schmiegelow, et al, American Journal of Pediatric Hematology Oncology 1990 and Dibenedetto et al, Pediatric Hematology Oncology 1994). We studied the effect of delays in therapy prior to maintenance by analyzing data from two HR-ALL clinical trials, CCG1961 and POG9906. The objective was to determine the association between time to maintenance (TTM) from starting induction therapy and event-free survival (EFS) in children with high-risk ALL. Methods: CCG1961 enrolled 2078 patients from September 1996 to May 2002 with B- and T-lineage ALL with high-risk features, defined as those aged 1–9 years with initial white blood cell count (WBC) ≥ 50,000/μl, any patient aged ≥ 10 years and ≤ 21 years, and those with central nervous system (CNS) leukemia or overt testicular leukemia. Rapid early responders (RERs), those with 〈 25% blasts in the bone marrow on day 7 of therapy, were randomized to receive standard or augmented BFM therapy with either a single interim maintenance and delayed intensification phase (SDI) or two interim maintenance and delayed intensification (DDI) courses as outlined in Table 1. Slow early responders (SERs) were randomized to augmented BFM with DDI with either doxorubicin or idarubicin and cyclophosphamide in the DI courses. POG9906 enrolled 276 patients from March 2000 to April 2003 with high-risk B-precursor ALL, defined as all patients with CNS disease, testicular disease, MLL rearrangement, age ≥ 16 years, or WBC ≥ 100K. In addition, it included selected patients aged 12–15 with high-risk disease based on the Shuster criteria for age and initial WBC. Patients with favorable cytogenetic features (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) were excluded unless they had CNS or testicular leukemia. Patients were treated with augmented BFM with DDI. Patients who made it to start of maintenance are included in this report. TTM was calculated as time from start induction until start of maintenance therapy. Expected TTM for those with B-lineage ALL is shown in Table 1. TTM was dichotomized by plotting the Akaike information criterion (AIC) versus all possible cutoff values of TTM and identifying the cut-point which best discriminated between groups who did and did not fail. The identified threshold was then examined as a predictor of EFS using the Kaplan Meier method and log rank test. The outcomes were 5-year EFS for CCG1961 and 4-year EFS for POG9906. Results: Among the B-lineage patients, longer TTM was significantly associated with improved EFS in CCG1961 Std BFM DI and SER Aug BFM Doxo arms, as well as on POG 9906. For example, in Std BFM DI, 5-year EFS was 83% in those with longer TTM and 71.9% in those with shorter TTM (P=.036). Among the T lineage cohort enrolled on CCG1961, similar results were seen with longer TTM being significantly associated with improved EFS in Std BFM DDI and SER Aug BFM Ida, and a trend toward improved EFS with longer TTM in each of the other arms. Conclusions: These data suggest that longer TTM may be associated with superior EFS in pediatric high-risk ALL. Multiple factors may contribute to this association. For instance, pharmacogenetic differences resulting in more treatment toxicity and delays may also be associated with more potent anti-leukemic effects, or patients with infectious complications may have an endogenous immune response that also has an anti-leukemia effect. Further research is needed to validate the association between TTM and EFS and to characterize the timing and causes of these delays in protocol therapy. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points Systemic antibacterial and granulocyte colony-stimulating factor prophylaxis appear to reduce bacterial infection rates. Mandatory hospitalization during profound neutropenia did not reduce infection or significantly reduce nonrelapse-related mortality.

Description: Abstract 2388 Acute myeloid leukemia (AML) is characterized by genomic abnormalities that impair differentiation and promote proliferation. There are known karyotypic alterations and somatic mutations associated with relapse risk, but are rarely predictive of response to induction chemotherapy. miRNAs are epigenetic regulators of cell cycle progression and proliferation and their altered expression can play roles in malignancy and cancer cell behavior. Aberrant expression of miRNAs has been implicated in AML pathogenesis and unique expression profiles have been established in specific subsets. Altered miR-181a and miR-155 expression was reported to correlate with specific cytogenetic and molecular characteristics and with clinical outcome. We inquired whether expression of miR-155 and miR-181a correlates with disease characteristics and clinical response in childhood AML. We evaluated diagnostic specimens from 175 AML patients with normal karyotype (NK) treated on COG AML trial AAML0531 for expression of the miRNAs by quantitative TaqMan MicroRNA Assays normalized against normal marrow. There was a 4 log-fold variation in miR-181a, and a 3 log-fold variation in miR-155 expression levels. Patients were divided into 4 quartiles (Q1-Q4) with Q1 consisting of patients with the lowest, and Q4 with the highest expression levels of the specific miRNA. We then correlated disease characteristics and clinical response across quartiles. There was no association of miR-181a or miR-155 expression with age, gender or race. For miR-155, patients in Q4 had a higher diagnostic WBC% than those in Q1-Q3 (60.4 vs. 23.3, p=0.003). Diagnostic bone marrow blast% for Q4 vs. Q1-Q3 was 83% vs. 65% (p=0.004). There was no correlation between miR-181a expression, for either diagnostic WBC (p=0.117) or bone marrow blast % (p=0.237). High miR-155 expression was accompanied by increased prevalence of FLT3-ITD mutations. 78% of patients in Q4 were FLT3-ITD+ vs. 27% in Q1-Q3 (p 〈 0.001). miR-155 expression was not associated with mutations in CEBPA (p=0.76), NPM1 (p=0.98) or WT1 (p=0.57) genes. With the high prevalence of FLT3-ITD, elevated miR-155 expression was associated with high-risk disease, where 50% in Q4 had high-risk disease vs. 12% in the Q1-Q3 (p

Description: Abstract 2740 Initial response to induction chemotherapy is a significant predictor of outcome in leukemias. Data from MRC10 AML trial demonstrated that patients (pts) with ≤15% blasts at the end of induction I (EOI1), as determined by morphologic analysis, had a similar outcome as those in morphologic complete remission (mCR, 15% blasts have a significantly diminished survival. The COG Phase III AML protocol AAML0531 has enrolled 968 eligible pts with de novo AML as of March 31, 2010. Those with 〉15% blasts by morphologic assessment (persistent disease, mPD) at EOI1 are considered a high-risk cohort; those with 5% to 15% blasts (partial remission, mPR) were included in the standard-risk group. As part of AAML0531, pts choose to enroll on a biology study to evaluate treatment response by multidimensional flow cytometry (MDF) after 2 courses of therapy (EOI1 and EOI2). Here we directly compared the morphologic bone marrow (BM) response at EOI1 in pts with mPR or mPD with that assessed by MDF and correlated the remission status at EOI1 to the mCR rate at EOI2. Of the 900 pts with evaluable response data at EOI1, 628 (70%) entered mCR; 104 (12%) had mPR; 126 (14%) had mPD; and 42 (5%) either died (n=19) or had refractory CNS AML (n=23). All pts, regardless of their blast %, were eligible to receive the second course of induction chemotherapy per protocol. Of those with mPD at EOI1 and evaluable data by EOI2, 65 (59%) entered mCR; 1 died; and 44 (40%) had mPD. At EOI1, 180 pts did not enter mCR (80 had mPR, and 100 had mPD). MDF evaluation of those 180 BM specimens showed that 74 (41%) had no evidence of disease by MDF at EOI1. Of those 74 pts, 69 (93%) entered mCR at EOI2. In contrast, mCR at EOI2 for those with any level of disease by MDF at EOI1 was 49% (p5% blasts by MDF (p=0.013). Because they are in different risk groups, pts with mPR and those with mPD were evaluated separately for the presence of disease by MDF. Median blast % in pts with mPR was 7% (range 5%-15%). Of the 76 pts with mPR at EOI1 with an evaluable EOI2 response, 19 (25%) did not enter mCR at EOI2. At EOI1, morphologic BM response was compared to that by MDF. Of the 80 pts in mPR at EOI1, 43 (54%) had no evidence of AML by MDF; 17 (21%) had 15%. In pts in mPR who did not have AML by MDF (n=43), 39 had remission status available by EOI2: 34 (87%) entered mCR, and 5 (13%) had refractory disease (〉5% blasts). Of the latter 5 patients, 4 had no evidence of disease by MDF. We subsequently evaluated BM status of the pts with PD by MDF at EOI1 and EOI2. Of those with mPD at EOI1, 62% entered mCR at EOI2. Of the 100 pts with mPD at EOI1 and MDF data for response evaluation, 31 had no evidence of disease by MDF, and all 25 with evaluable response by EOI2 entered mCR. In the remaining 69 pts, the presence of AML by MDF ranged from 0.05% to 95% (median 22%). Patients with mPD at EOI1 with any level of disease by MDF had a mCR rate of 41% at EOI2. Of the 16 pts with mPD and 0.5% to 4.9% blasts by MDF at EOI1, 14 had an evaluable EOI2 response: 11 (79%) entered mCR; 2 (18%) experienced treatment failure at EOI1; and 1 suffered extramedullary relapse. When the EOI1 evaluation was limited to the 53 patients with '5% blasts by MDF, the mCR rate at EOI2 was 30%. This study demonstrates a substantial discrepancy between morphologic and MDF assessments of induction BM specimens and highlights the need to implement MDF for accurate evaluation of remission status. We further demonstrate that a blast threshold of 5% by MDF at EOI1 may be an accurate predictor of response to the second course of therapy. Disclosures: No relevant conflicts of interest to declare.