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Biomedical subjects

Todd A Alonzo

Publications and source records attributed to Todd A Alonzo.

13 recordsLinked to original sources
PubMed2025

EZH2-driven immune evasion at disease presentation defines a targetable high-risk subset of acute leukemia exemplified by t(16;21) FUS::ERG AML.

The past 25 years of clinical trials have produced few improvements in pediatric AML (pAML) outcomes. This is acutely evident in patients with t(16;21)(p11;q22), yielding FUS::ERG. Patients with FUS::ERG-positive AML relapse quickly and do not respond to transplantation. Major histocompatibility complex (MHC) class I & II receptors and costimulatory molecules are absent at diagnosis in FUS::ERG-positive AML, mirroring the phenotype and outcomes of post-transplant relapse. We show that this is driven by overexpression of EZH2, in vitro and in multiple clinical cohorts. While FUS::ERG AML is the most extreme example, this phenotype is shared by lethal CBFA2T3::GLIS2-driven AML, and patients with RUNX1::RUNX1T1 have significantly worse outcomes when EZH2 overexpression co-occurs. The FDA-approved EZH2 inhibitor tazemetostat reverses this phenotype, re-establishes MHC presentation, and elicits immune effector cell-mediated elimination. EZH2 inhibitors may provide the first targeted therapeutic frontline option for AML patients with FUS::ERG, with the potential for broader frontline immunostimulatory benefits.

Journal Article↗
PubMed2003

Mitoxantrone and cytarabine induction, high-dose cytarabine, and etoposide intensification for pediatric patients with relapsed or refractory acute myeloid leukemia: Children's Cancer Group Study 2951.

PURPOSE: To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. PATIENTS AND METHODS: Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. RESULTS: Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). CONCLUSION: Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.

Adolescent↗
PubMed2003

Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891.

PURPOSE: To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors. PATIENTS AND METHODS: Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Children's Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine. RESULTS: Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P <.001), with more megakaryocytic leukemia (70% v 6%; P <.001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P <.001). Equivalent grade 3 to 4 toxicity (29% v 30%; P =.84) was seen, though children with DS had greater pulmonary toxicity (P <.01) during induction and mucositis during intensification (P =.12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P <.0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P =.006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P =.002). CONCLUSION: Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

Acute Disease↗
PubMed2003

Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia.

Activating mutations of receptor tyrosine kinases (RTKs) and their downstream affectors are common in acute myeloid leukemia (AML). We performed mutational analysis of FLT3, c-kit, c-fms, vascular endothelial growth factor (VEGF) receptors (Flt-1, KDR [kinase domain receptor]), and ras genes in a group of 91 pediatric patients with AML treated on Children's Cancer Group clinical trial CCG-2891. Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes. Mutation-positive patients had a higher median diagnostic white blood cell (WBC) count (71.5 vs 19.6 x 10(9)/L; P =.005) and lower complete remission rate (55% versus 76%; P =.046) than mutation-negative patients. The Kaplan-Meier estimate of overall survival (OS) for patients with and without an activating mutation was 34% versus 57%, respectively (P =.035). However, within this group, patients with FLT3/ALM (activation loop mutation) had good outcomes (OS, 86%). Exclusion of the FLT3/ALM from analysis decreased the OS for the remaining mutation-positive patients to 26% (P =.003). Ten of the 23 mutation-positive and 11 of the 34 mutation-negative patients received an allogeneic bone marrow transplant (BMT) in first complete remission (CR). In the mutation-positive group, the disease-free survival (DFS) for the allogeneic BMT recipients was 72% versus 23% for the 13 patients who received chemotherapy or autologous BMT (P =.01). DFS for the mutation-free patients with and without allogeneic BM transplantation was 55% and 40%, respectively (P =.38). Activating mutations in the RTK/ras signaling pathway are common in pediatric AML, and their presence may identify a population at higher risk of poor outcome who may benefit from allogeneic BM transplantation.

Adolescent↗
PubMed2003

Estimating disease prevalence in two-phase studies.

Disease prevalence is ideally estimated using a 'gold standard' to ascertain true disease status on all subjects in a population of interest. In practice, however, the gold standard may be too costly or invasive to be applied to all subjects, in which case a two-phase design is often employed. Phase 1 data consisting of inexpensive and non-invasive screening tests on all study subjects are used to determine the subjects that receive the gold standard in the second phase. Naive estimates of prevalence in two-phase studies can be biased (verification bias). Imputation and re-weighting estimators are often used to avoid this bias. We contrast the forms and attributes of the various prevalence estimators. Distribution theory and simulation studies are used to investigate their bias and efficiency. We conclude that the semiparametric efficient approach is the preferred method for prevalence estimation in two-phase studies. It is more robust and comparable in its efficiency to imputation and other re-weighting estimators. It is also easy to implement. We use this approach to examine the prevalence of depression in adolescents with data from the Great Smoky Mountain Study.

Adolescent↗
PubMed2003

Prognostic implications of t(10;11) translocations in childhood acute myelogenous leukemia: a report from the Children's Cancer Group.

PURPOSE: This was a retrospective analysis of outcome based on cytogenetics for a Children's Cancer Group phase 3 trial of acute myelogenous leukemia (AML) (CCG-2891). PATIENTS AND METHODS: A retrospective analysis of outcome for newly diagnosed children with AML and myelodysplastic syndrome (MDS) was performed using data collected from CCG-2891. The authors identified 11 patients whose blasts carried t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q among 470 eligible patients entered with acceptable, centrally reviewed cytogenetics. A bone marrow specimen was used for each case of cytogenetic analysis in which 20 banded (either G-banded or Q-banded) metaphases were completed on each subject. All 11 patients had characteristic monocytoid morphology (M4 or M5) and tended to be young (0.1-7.9 years; median 0.9 years). RESULTS: All 11 patients entered remission, but remissions tended to be short; 9 patients relapsed within 12 months (median 4 months). The relapse rate of 82% was significantly higher for this group of patients compared with 46% for the group at large. The relapse rate for this group of patients having t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was also significantly higher compared with subjects with other 11q23 chromosomal abnormalities. The CNS relapse rate of 55% was higher for this group of patients compared with 3% for all other patients in the study. The CNS relapse rate was higher for the subjects who had t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q compared with subjects with all other chromosome 11 abnormalities. Three children survived, two in second remissions (4.7 and 6.3 years after relapse) and one in first remission (7.0 years after diagnosis). Survival and event-free survival for the patients with t(10;11) reciprocal translocations or other complex rearrangements involving 10p and 11q was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from all other patients with cytogenetics. Similarly, the survival and event-free survival for the patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 was 27 +/- 27% and 9 +/- 17% at 6 years, respectively, and was not statistically different from the 11q23 group of subjects. CONCLUSIONS: Further research is needed to determine the various changes that are occurring at the molecular level for patients with t(10;11) translocations and other rearrangements of chromosomes 10 and 11 to gain insight into the mechanisms causing this clinical phenotype associated with a poor prognosis.

Child↗
PubMed2002

Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children's Cancer Group study of 252 patients with acute myeloid leukemia.

Approximately 40% of children with acute myeloid leukemia (AML) who respond to initial therapy subsequently relapse. Multidimensional flow cytometry employing a standardized panel of monoclonal antibodies enables the detection of small numbers of occult leukemic cells that persist during therapy using technology adaptable by most clinical laboratories. We performed a prospective, blinded evaluation of bone marrow specimens obtained from 252 pediatric patients with de novo AML to determine whether detection of occult leukemia defined as more than or equal to 0.5% blasts with aberrant surface antigen expression as determined by flow cytometry was predictive of subsequent relapse. Occult leukemia was detected in 41 (16%) of the 252 patients who responded to initial induction therapy. In time-dependent multivariate analyses that controlled for allogeneic marrow transplantation, variable intervals between sample submission, age, sex, white blood cell count at diagnosis, presence of splenomegaly or hepatomegaly, and presence of more than 15% blasts in the marrow after the first course of induction, patients harboring occult leukemia were 4.8 times more likely to relapse (95% confidence interval [CI] = 2.8 to 8.4, P <.0001) and 3.1 times more likely to die (95% CI; 1.9 to 5.1, P <.0001) than those lacking leukemia detectable by flow cytometry. In this analysis, flow cytometric evidence of leukemia after the initiation of therapy emerged as the most powerful independent prognostic factor associated with poor outcome. Among patients in whom a marrow sample was available for analysis at the end of consolidation therapy, overall survival at 3 years was 41% versus 69% for patients with and without occult leukemia, respectively (P =.0058).

Acute Disease↗
PubMed2002

Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation.

There has not been a reported series of children with therapy-induced myelodysplastic syndrome/acute myeloid leukemia (tMDS/tAML) who were treated systematically. This paper describes 24 children with tMDS/tAML who were assigned randomly to standard- or intensive-timing induction on protocol CCG 2891. Presenting features and outcomes of those children were compared with those of 960 patients with de novo MDS (62 patients) or AML (898 patients). Children with tMDS/tAML were older at presentation (P =.015), had lower white blood cell counts (P =.01), and were more likely to have MDS (21% vs 7%) (P =.02) and trisomy 8 (P =.06). Fewer had hepatomegaly (P =.02), splenomegaly (P =.03), hepatosplenomegaly (P =.02), or classic AML translocations [t(8;21), t(15;17), 16q22; P =.02]. They had a poorer induction rate (50% vs 72%, P =.016), overall survival (26% vs 47% at 3 years, P =.007), and event-free survival (21% vs 39% at 3 years, P =.023). Disease-free survival after achieving remission was similar (45% vs 53%, P =.868). Children with tMDS/tAML who received intensive-timing induction had better outcomes than those who received standard-timing induction (overall survival 32% vs 0%, P =.54). In this study, the latency period to development of tMDS/tAML was the same for presumed alkylator-induced as for topoisomerase-induced myeloid leukemia. The findings of this study confirm that most children with tMDS/tAML have disease resistant to current therapies. Standard-timing induction appears less effective for this population.

Acute Disease↗
PubMed2002

Sample size calculations for comparative studies of medical tests for detecting presence of disease.

Technologic advances give rise to new tests for detecting disease in many fields, including cancer and sexually transmitted disease. Before a new disease screening test is approved for public use, its accuracy should be shown to be better than or at least not inferior to an existing test. Standards do not yet exist for designing and analysing studies to address this issue. Established principles for the design of therapeutic studies can be adapted for studies of screening tests. In particular, drawing upon methods for superiority and non-inferiority studies of therapeutic agents, we propose that confidence intervals for the relative accuracy of dichotomous tests drive the design of comparative studies of disease screening tests. We derive sample size formulae for a variety of designs, including studies where patients undergo several tests and studies where patients receive only one of the tests under evaluation. Both cohort and case-control study designs are considered. Modifications to the confidence intervals and sample size formulae are discussed to accommodate studies where, because of the invasive nature of definitive testing, true disease status can only be obtained for subjects who are positive on one or more of the screening tests. The methods proposed are applied to a study comparing a modified pap test to the conventional pap for cervical cancer screening. The impact of error in the gold standard reference test on the design and evaluation of comparative screening test studies is also discussed.

Case-Control Studies↗
PubMed2002

Prospective study of 90 children requiring treatment for juvenile myelomonocytic leukemia or myelodysplastic syndrome: a report from the Children's Cancer Group.

PURPOSE: We report the first large prospective study of children with myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) treated in a uniform fashion on Children's Cancer Group protocol 2891. PATIENTS AND METHODS: Ninety children with JMML, various forms of MDS, or acute myeloid leukemia (AML) with antecedent MDS were treated with a five-drug induction regimen (standard or intensive timing). Patients achieving remission were allocated to allogeneic bone marrow transplantation (BMT) if a matched family donor was available. All other patients were randomized between autologous BMT and aggressive nonmyeloablative chemotherapy. Results were compared with patients with de novo AML. RESULTS: Patients with JMML and refractory anemia (RA) or RA-excess blasts (RAEB) exhibited high induction failure rates and overall remission of 58% and 48%, respectively. Remission rates for patients with RAEB in transformation (RAEB-T) (69%) or antecedent MDS (81%) were similar to de novo AML (77%). Actuarial survival rates at 6 years were as follows: JMML, 31% +/- 26%; RA and RAEB, 29% +/- 16%; RAEB-T, 30% +/- 18%; antecedent MDS, 50% +/- 25%; and de novo AML, 45% +/- 3%. For patients achieving remission, long-term survivors were found in those receiving either allogeneic BMT or chemotherapy. The presence of monosomy 7 had no additional adverse effect on MDS and JMML. CONCLUSION: Childhood subtypes of MDS and JMML represent distinct entities with distinct clinical outcomes. Children with a history of MDS who present with AML do well with AML-type therapy. Patients with RA or RAEB respond poorly to AML induction therapy. The optimum treatment for JMML remains unknown.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Distribution-free ROC analysis using binary regression techniques.

Receiver operating characteristic (ROC) regression methodology is used to identify factors that affect the accuracy of medical diagnostic tests. In this paper, we consider a ROC model for which the ROC curve is a parametric function of covariates but distributions of the diagnostic test results are not specified. Covariates can be either common to all subjects or specific to those with disease. We propose a new estimation procedure based on binary indicators defined by the test result for a diseased subject exceeding various specified quantiles of the distribution of test results from non-diseased subjects with the same covariate values. This procedure is conceptually and computationally simplified relative to existing procedures. Simulation study results indicate that the approach has fairly high statistical efficiency. The new ROC regression methodology is used to evaluate childhood measurements of body mass index as a predictive marker of adult obesity.

Journal Article↗
PubMed2002

Impact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children's Cancer Group.

PURPOSE: To determine whether granulocyte colony-stimulating factor (G-CSF) administered during acute myelogenous leukemia (AML) induction affects hematopoietic and nonhematopoietic toxicity, length and outcome of induction therapy, event-free survival, overall survival, and prognostic significance of the day 7 bone marrow. PATIENTS AND METHODS: In Children's Cancer Group study 2891, patients were given intensively timed induction with G-CSF (n = 254) after accrual for the regimen without G-CSF (n = 258) was met. RESULTS: Time to neutropenic recovery after induction courses 1 and 2 was significantly shorter for patients who received G-CSF. Times to platelet recovery were similar regardless of G-CSF use. Effects on incidence of grades 3 and 4 toxicities, infections, or fatal infections were not observed. Use of G-CSF reduced the median length of induction by 9 days and hospital stay by 6 days. Induction remission rates, overall survival, and event-free survival were similar with and without G-CSF. Day 7 bone marrow was prognostic of better long-term outcome. Patients with hypercellular day 7 marrow who received G-CSF had a higher remission rate and event-free survival than patients who did not receive G-CSF. CONCLUSIONS: The incidence of severe toxic event and infection, induction remission rate, overall survival, and event-free survival were comparable regardless of G-CSF use. Use of G-CSF decreased neutropenia duration, hospital stay, and length of induction. Patients with hypercellular day 7 bone marrow who received G-CSF had an induction remission rate and event-free survival superior to those of patients who did not receive G-CSF.

Acute Disease↗