Pediatric LSC3 (pLSC3) Score Derived from DNMT3B-CD34-GPR56 As a Prognostic Tool to Predict AML Patient Outcome: Results from Two Independent Pediatric AML Cohorts

Abstract Introduction: Resistance and relapse remain major obstacles in the treatment of acute myeloid leukemia (AML). Pre-existence and persistence of drug resistant leukemia stem cells (LSCs) is considered one of the major causes of relapse. A previous study (Ng et al., 2016) reported a prognostic signature of 17 genes (LSC17 score) differentially expressed in LSC+ compared to LSC- cell fractions that predicted outcome in patients with AML thereby classifying patients into high and low risk groups. The goal of this study is to determine the validity of LSC17 score in pediatric AML patients and to enhance its clinical utility by exploring a new score with limited number of stem cell genes. Methods: 150 pediatric patients with AML enrolled in the multicenter AML02 clinical trial (ClinicalTrials.gov Identifier: NCT00136084) with Affymetrix U133A microarray gene expression data and clinical data were included in the study. Since only 14 of the 17 genes were represented on the Affymetrix U133A gene chip we tested the validity of the LSC14 score using the previously defined equation (Ng et al, 2016) with multiple clinical endpoints such as minimum residual disease (MRD), event free survival (EFS) and overall survival (OS). To reduce the model complexity, we applied a penalized regression algorithm called the least absolute shrinkage and selection operator (LASSO) implemented in the glmnet R-package using event free survival (EFS) as an outcome variable. Score of the new equation, which included three genes, was designated as pediatric-LSC3 (pLSC3). pLSC3 was tested in the AML02 cohort for association of high or low pLSC3 (based on the median value) with clinical endpoints mentioned above. pLSC3 score equation was validated using publically available gene-expression data from 117 pediatric relapse enriched AML patient cohort enrolled in Children's Oncology Group (COG) protocol (TARGET database). COX-proportional hazard models and Log rank test were used for survival data analysis. Results: AML02 cohort: Patients with high LSC14 scores (greater than median), had significantly worse MRD (p<0.0001), EFS (HR = 3.72, P <0.00001) and OS (HR = 4.85, P <0.00001) compared to patients with low LSC14 scores. After applying LASSO regression to simplify the score equation, only three genes (DNMT3B, CD34 and GPR56) remained significant to the model fit of the EFS data thus we created a pLSC3 with coefficients as described in the equation: pLSC3_SCORE = (DNMT3B*0.0431) + (CD34*0.00076) + (GPR56*0.0326). Patients were classified as high or low pLSC3 and patients with high pLSC3 scores had significantly worse EFS (HR=3.595, P < 0.0001; Figure 1A) and OS (HR= 4.53, P<0.0001) and higher MRD after induction 1 and induction II, respectively (P<0.00001 and p=0.0001 respectively; Figure 1C). These results were further validated in an independent cohort of patients from TARGET database, where higher pLSC3 score was associated with worse EFS, OS and MRD (EFS: HR=1.64, P=0.0248; Figure 1B, OS: HR = 1.77, P = 0.0349 and MRD p=0.0002, Figure 1D). Consistent results were also observed with high pLSC3 predictive of significantly worse outcome within standard risk group patients within both AML02 and COG cohorts (AML02-EFS: HR = 2.97, P = 0.0153, COG-EFS: HR = 2.22, P = 0.0096; Figure 1E and F respectively). In a multivariate COX regression model, pLSC3 score groups was the only significant covariate (table 1). It explained 13.1% of variability in EFS and 11.6% of variability in OS, while other prognostic factors such as risk groups, FLT3 status, treatment arm and age collectively explained 15.1 and 12.1 % of variability. Discussion: In summary, our results show validity of a previously defined LSC14 score in a pediatric AML population from the multicenter AML02 clinical trial. To enhance the clinical utility, score equation was further simplified and the final score (pLSC3) was derived from three genes: DNMT3B, which encodes for DNA methyltransferase; CD34, an important cell surface marker for early-undifferentiated LSCs; and GPR56, a G protein coupled receptor of significance in AML. Given that there is need to refine classification of a highly heterogeneous group of patients with standard risk AML, we show that differentiating standard risk patients based on pLSC3 score should be considered in the future. We show the relevance of pLSC3 in two independent cohorts, opening up opportunities to improve treatment outcomes of pediatric patients with AML. Disclosures No relevant conflicts of interest to declare.

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Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002

Journal of Clinical Oncology ◽

10.1200/jco.2013.48.6522 ◽

2014 ◽

Vol 32 (3) ◽

pp. 174-184 ◽

Cited By ~ 127

Author(s):

Jan Stary ◽

Martin Zimmermann ◽

Myriam Campbell ◽

Luis Castillo ◽

Eduardo Dibar ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Standard Treatment ◽

Lymphoblastic Leukemia ◽

Risk Groups ◽

Childhood Acute Lymphoblastic Leukemia ◽

Event Free Survival ◽

Free Survival ◽

Early Treatment Response ◽

The Impact ◽

Standard Risk

Purpose From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. Patients and Methods For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster [BFM] option). Results At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. Conclusion The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.

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Results of two consecutive treatment protocols in Polish children with acute lymphoblastic leukemia

Scientific Reports ◽

10.1038/s41598-020-75860-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Joanna Zawitkowska ◽

Monika Lejman ◽

Michał Romiszewski ◽

Michał Matysiak ◽

Magdalena Ćwiklińska ◽

...

Keyword(s):

Medical Records ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

Risk Groups ◽

Event Free Survival ◽

Treatment Protocols ◽

Free Survival ◽

Impact On Survival ◽

Oncological Centers

AbstractThe aim of the study was to retrospectively compare the effectiveness of the ALL IC-BFM 2002 and ALL IC-BFM 2009 protocols and the distribution of risk groups by the two protocols after minimal residual disease (MRD) measurement as well as its impact on survival. We reviewed the medical records of 3248 patients aged 1–18 years with newly diagnosed ALL who were treated in 14 hemato-oncological centers between 2002 and 2018 in Poland. The overall survival (OS) of 1872 children with ALL treated with the ALL IC 2002 protocol was 84% after 3 years, whereas the OS of 1376 children with ALL treated with the ALL IC 2009 protocol was 87% (P < 0.001). The corresponding event-free survival rates were 82% and 84% (P = 0.006). Our study shows that the ALL IC-BFM 2009 protocol improved the results of children with ALL compared to the ALL IC-BFM 2002 protocol in Poland. This analysis confirms that MRD marrow assessment on day 15 of treatment by FCM-MRD is an important predictive factor.

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CD2 antigen expression on leukemic cells as a predictor of event-free survival after chemotherapy for T-lineage acute lymphoblastic leukemia: a Children's Cancer Group study

Blood ◽

10.1182/blood.v88.11.4288.4288 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4288-4295 ◽

Cited By ~ 3

Author(s):

FM Uckun ◽

PG Steinherz ◽

H Sather ◽

M Trigg ◽

D Arthur ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Antigen Expression ◽

Leukemic Cells ◽

Event Free Survival ◽

Free Survival ◽

Cancer Group ◽

Standard Risk

Abstract We examined the prognostic impact of CD2 antigen expression for 651 patients with T-lineage acute lymphoblastic leukemia (ALL), who were enrolled in front-line Childrens Cancer Group treatment studies between 1983 and 1994. There was a statistically significant correlation between the CD2 antigen positive leukemic cell content of bone marrow and probability of remaining in bone marrow remission, as well as overall event-free survival (EFS) (P = .0003 and P = .002, log-rank tests for linear trend). When compared with patients with the highest CD2 expression level (> 75% positivity), the life table relative event rate (RER) was 1.22 for patients with intermediate range CD2 expression level (30% to 75% positivity) and 1.81 for “CD2-negative” patients (< 30% positivity). At 6 years postdiagnosis, the EFS estimates for the three CD2 expression groups (low positivity to high positivity) were 52.8%, 65.5%, and 71.9%, respectively. CD2 expression remained a significant predictor of EFS after adjustment for the effects of other covariates by multivariate regression, with a RER of 1.47 for CD2- negative patients (P = .04). Analysis of T-lineage ALL patients shows a significant separation in EFS after adjustment for the National Cancer Institute (NCI) age and white blood cell (WBC) criteria for standard and high-risk ALL (P = .002, RER = 1.67). The determination of CD2 expression on leukemic cells helped identify patients with the better and poorer prognoses in both of these risk group subsets. For standard risk T-lineage ALL, CD2-negative patients had a worse outcome (P = .0007, RER = 2.92) with an estimated 5-year EFS of 55.9% as compared with 78.3% for the CD2-positive patients. Thus, CD2 negativity in standard risk T-lineage ALL identified a group of patients who had a worse outcome than high-risk T-lineage ALL patients who were CD2 positive. The percentage of CD2 antigen positive leukemic cells from T- lineage ALL patients is a powerful predictor of EFS after chemotherapy. This prognostic relationship is the first instance in which a biological marker in T-lineage ALL has been unequivocally linked to treatment outcome.

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MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2017.74.7451 ◽

2017 ◽

Vol 35 (35) ◽

pp. 3964-3977 ◽

Cited By ~ 20

Author(s):

Emilia L. Lim ◽

Diane L. Trinh ◽

Rhonda E. Ries ◽

Jim Wang ◽

Robert B. Gerbing ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Oxidative Phosphorylation ◽

Treatment Failure ◽

Myeloid Leukemia ◽

Outcome Prediction ◽

Classification Scheme ◽

Event Free Survival ◽

Free Survival ◽

Pediatric Aml ◽

Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

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Treatment of 11q23/MLL + AML with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

Blood ◽

10.1182/blood.v126.23.799.799 ◽

2015 ◽

Vol 126 (23) ◽

pp. 799-799

Author(s):

Jessica Pollard ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

Susana C. Raimondi ◽

Betsy A. Hirsch ◽

...

Keyword(s):

Clinical Outcomes ◽

Gemtuzumab Ozogamicin ◽

Phase Iii ◽

Study Entry ◽

Cell Transplant ◽

Event Free Survival ◽

Conventional Chemotherapy ◽

Free Survival ◽

Pediatric Aml ◽

To Receive

Abstract CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is the target of gemtuzumab ozogamicin (GO). We previously demonstrated the clinical benefit of GO treatment in children with AML treated on COG AAML0531 in which patients were randomized to receive standard Medical Research Council-based chemotherapy with or without GO. We also demonstrated that CD33 expression is highly variable in pediatric AML and that children with 11q23 translocations involving the KMT2A gene, previously known as the mixed lineage leukemia gene and referred to here as MLL+, have significantly higher CD33 expression, as defined by mean fluorescent intensity (MFI) values, than patients without 11q23/MLL + leukemia (MLL-) [median CD33 MFI: MLL + 229.13 (range 6-1351) vs. MLL-129 (range 2.68-1225.87) P <0.001.] Given significantly elevated levels of CD33 expression in MLL + AML and our previous findings showing an association between high CD33 expression and improved response to GO, we evaluated MLL + AML patients treated on COG AAML0531 to determine whether GO treatment improved their clinical outcomes. COG AAML0531 included 1022 eligible patients ages 1 month-29.99 years of which 215 harbored a 11q23/MLL rearrangement that was confirmed by central cytogenetic review (including G-banding and FISH). Analysis of overall outcomes revealed similar complete remission (CR) rates after Induction I for MLL + and MLL-patients (71% vs. 73%, P = 0.494). However, MLL + patients had lower 5-year overall survival (OS) and event-free survival (EFS) than MLL-patients (OS 58% vs. 66%, P =0.012, EFS 38% vs. 51%, P =<0.001) as well as higher rates of relapse (RR) (52% vs. 36%, P =<0.001) and lower disease-free survival (DFS) (46% vs. 58%, P =0.002). Of the 215 MLL + patients, 107 were treated with conventional chemotherapy only (No-GO) and 108 with chemotherapy and GO (GO). CD33 expression data from flow cytometry analysis were available for 170 MLL + patients. The median CD33 MFI was similar for MLL + patients on both treatment arms [No-GO: 226.5 (range 6-911), GO 237.345 (range 7.6-1351), P = 0.648]. CR rate was higher for MLL + patients treated with GO vs. No-GO (77% vs. 64%; P =0.035). Evaluation of clinical outcomes for patients in the MLL + cohort by treatment arm revealed a superior outcome for GO recipients. EFS at 5 years from study entry was 48% for patients in the GO group vs. 28% for those in the No-GO group (P =0.002) with a corresponding OS of 64% vs. 53% (P =0.053). MLL-patients had similar EFS and OS regardless of GO exposure (P =0.435 and P =0.861, respectively, Figure 1). In MLL + patients who achieved CR, GO exposure translated to lower RR (40% vs. 66% No-GO, P =0.001) and improved DFS (57% vs. 33% No-GO, P =0.002) demonstrating that MLL + patients receiving GO treatment have improved outcomes. In COG AAML0531 a subset of patients was allocated to receive allogeneic hematopoietic stem cell transplant (HSCT) in 1st CR based on donor availability and risk status. This allowed us to evaluate the effect of HSCT in MLL+ patients in the context of GO exposure as any MLL+ patient with a matched family donor or poor induction response (>15% blasts) underwent HSCT. HSCT was conducted in 19 of 83 MLL+ patients (23%) in the GO group after one course of intensification therapy and in 11 of 73 (15%) patients in the No-GO group. Patients in the GO group who received HSCT consolidation had better outcomes than those not receiving HSCT. Specifically, MLL+ patients who received HSCT after prior treatment with GO had a RR of 28% at 5 years from HSCT compared with a RR of 73% for MLL + patients who received HSCT without GO prior (P =0.006). The corresponding DFS at 5 years from HSCT for patients in the GO and No-GO groups was 72% vs. 27% (P =0.004) respectively. These results highlight that the clinical impact of induction GO maintains clinical significance in the post-HSCT setting. Our analysis of data from AAML0531 suggests that pediatric MLL + AML might benefit from the addition of GO to conventional chemotherapy. HSCT might further enhance GO benefit in this subset of patients. Future studies, utilizing GO or other novel CD33 targeted agents, should be considered for MLL + pediatric AML given the superior outcomes observed. Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Figure 1. Event-free survival from study entry for 11q23/MLL + vs. MLL - patients by treatment arm (GO vs. No-GO). Disclosures Aplenc: Sigma Tau: Honoraria. Loken:Hematologics Inc.: Equity Ownership.

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Update of the FL2000 randomized trial combining rituximab to CHVP-Interferon in follicular lymphoma (FL) patients (pts)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7508 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7508-7508 ◽

Cited By ~ 21

Author(s):

C. Foussard ◽

N. Mounier ◽

A. Van Hoof ◽

V. Delwail ◽

O. Casasnovas ◽

...

Keyword(s):

Overall Survival ◽

Randomized Study ◽

Bone Marrow Involvement ◽

Risk Groups ◽

Tumor Burden ◽

Event Free Survival ◽

Free Survival ◽

High Tumor Burden ◽

Ecog Ps

7508 Background: The GELA-GOELAMS FL2000 trial investigated the role of rituximab in the first line treatment of FL pts. Methods: This prospective randomized study compared the CHVP regimen (12 courses) +18 months α2b-IFN (CHVP-I) to 6 CHVP courses combined with 6 rituximab infusions + 18 months IFN (R-CHVP-I). The primary endpoint was event-free survival (EFS). Inclusion criteria consisted in untreated stage II-IV FL pts; 18–75 years old; with a high tumor burden defined by at least one of the following criteria: B symptoms, ECOG PS>1, LDH>normal value, β2-microglobulin ≥3 mg/L, largest tumor ≥7 cm, 3 distinct nodes ≥3 cm, serous effusion, compression or symptomatic spleen enlargement. Results: From 05/00 until 05/02, 358 eligible pts were randomized (CHVP-I 183 pts and R-CHVP-I 175 pts) with the following characteristics: M/F = 1; median age = 60 years [25–75]; ECOG > 1 = 8%; B symptoms = 27%; AA stage > II = 87%; bone marrow involvement = 58%; β2-m ≥3 mg/L = 31%; LDH > N = 37%; Hb <12 g/dL = 18%; FLIPI score ≥3 in 57% of the pts. The first analysis [ASH 2004] showed a significant better treatment response in R-CHVP-I as compared to CHVP-I and a improvement of event free survival (EFS) in the R-CHVP-I arm (Log-Rang, P = .003). As initially planned, a second analysis on all pts has now been performed with a median follow-up of 3½ years, all pts with data >01/01/05. The median EFS for the whole population has not yet been reached. In the CHVP-I arm, median EFS was 3 years and 46% of the pts are event-free at 42 months (mo.). In contrast, the median has not been reached in the R-CHVP-I arm and the EFS is 67% at 42 mo. (P < .0001). This improvement in EFS was found both in the 150 pts with a low or intermediate FLIPI score (P = .019) and in those (n = 201) with a high score (P = .0005). When considering the 230 pts responders at the end of 18 mo. of therapy, 42 mo. EFS is 62% in CHVP-I arm versus 81% in R-CHVP-I arm (P = .002). Finally, the overall survival at 42 mo. of patients in the CHVP-I arm is of 84% versus to 91% in the R-CHVP-I arm (P = .029) with a reduction of death risk by approximately 2 (RR = 0.55). Conclusions: These results demonstrate that rituximab combined with CHVP-I has a durable benefit, in all FLIPI risk groups, allows to reduce the duration of chemotherapy and improves overall survival in high-tumor burden FL pts. [Table: see text]

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Augmented Berlin-Frankfurt-Muenster (ABFM) regimen for children with standard-risk acute lymphoblastic leukemia (SR-ALL) and slow early response (SER)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9511 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9511-9511

Author(s):

Y. H. Matloub ◽

A. Angiolillo ◽

B. Bostrom ◽

L. Stork ◽

S. P. Hunger ◽

...

Keyword(s):

Negative Impact ◽

Lymphoblastic Leukemia ◽

Early Response ◽

Event Free Survival ◽

Eligibility Criteria ◽

Standard Regimen ◽

Free Survival ◽

E Coli ◽

Cancer Group ◽

Standard Risk

9511 Background: Numerous studies have shown that SER in ALL has a negative impact on outcome. Children's Cancer Group CCG-1882 demonstrated that post-induction intensification greatly improved the outcome of children with high-risk ALL and SER. Five year event-free-survival (EFS), and overall survival (OS) for the augmented regimen was 75 ± 4% vs 55 ± 4.5%, and 78 ± 4% vs 67 ± 5% for the standard regimen, p <0.001 and 02 respectively (N Engl J Med 1998; 338:1663–71). Methods: Therefore, COG-1952 and COG- 1991, studies for patients with SR-ALL, assigned the slow early responders to augmented therapy, while others were randomized according to the study design. Study eligibility criteria were similar for both, and included newly diagnosed children with National Cancer Institute SR criteria. COG-1952 accrued a total of 2,027 patients and COG-1991 accrued 3,054. In COG-1952 patients were deemed SER if their day-7 marrow had >5% blasts, and their day-14 marrow >25%. COG-1991 used the same criteria for SER, but also added patients whose day-7 marrow had >25% blasts and their day-14 marrow had >5% blasts to the SER group. This was based on the unfavorable outcome of this subgroup in COG-1952. The augmented therapy in COG-1991 like the CCG-1882 and COG-1952, was based on a COG-modified ABFM, but differed in using dexamethasone as the sole steroid and pegylated asparaginase as the asparaginase preparation, as compared to prednisone in induction and maintenance, and native E coli asparaginase. Results: Comparative groups with days 7 and 14 M3 marrows and unfavorable cytogenetics included 126 patients from COG-1991 and 81 from the COG-1952 were assigned to their corresponding ABFM regimens. Four year EFS and OS were 85% ± 5% and 90 ± 4% for CCG-1991 vs 61 ± 5.6% and 75 ± 5% for CCG-1952, p = 0.003 and 0.04 respectively. Conclusion: We conclude that the use of dexamethasone, and pegylated asparaginase greatly improves the outcome of children with NCI-SR with SER treated on a modified augmented BFM therapy, thus supporting the use of these agents in ALL therapy. No significant financial relationships to disclose.

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Clinical value of event-free survival (EFS) in acute myeloid leukemia (AML).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18513 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18513-e18513

Author(s):

Abhishek Maiti ◽

Hagop M. Kantarjian ◽

Vinita Popat ◽

Carlos Blanco ◽

Miguel Velasquez ◽

...

Keyword(s):

Myeloid Leukemia ◽

Blood Product ◽

Risk Groups ◽

Care Utilization ◽

Newly Diagnosed ◽

Inclusion Criteria ◽

Event Free Survival ◽

Imaging Studies ◽

Clinical Value ◽

Free Survival

e18513 Background: EFS is not considered a robust end-point for AML trials. We hypothesized that rather than a surrogate for overall survival (OS), improvement in EFS may be valuable due to patients (pts) staying in remission and thus decreasing health care utilization (HCU). Methods: In this retrospective study we identified AML pts treated on frontline therapy trials at our institute from 2003-2013 with EFS ≥2 months (mo) and OS of 12-36 mo. We captured the amount of HCU from diagnosis till death, including number of clinic and emergency room (ER) visits, hospitalizations, consultations, blood product transfusions, invasive procedures, laboratory and imaging studies. Linear regression and product-moment correlation were used to determine the relation between these parameters and EFS. Results: Among 337 pts meeting inclusion criteria, the median age was 65 years, 30% had adverse risk AML, 47% received intensive chemotherapy (IC) and 27% received hypomethylating agents (HMA). The median EFS was 10.8 mo. Increasing EFS led to statistically significant decline in HCU for all patients regardless of OS and the correlations were stronger for pts achieving a complete remission (CR, Table). These observations held true across European LeukemiaNet risk groups, younger and older pts, and those receiving IC, HMA, and non-IC, with or without other agents. Conclusions: In newly diagnosed AML, improvement in EFS is correlated with decrease in all HCU irrespective of OS duration. [Table: see text]

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Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

Blood ◽

10.1182/blood-2011-07-364661 ◽

2011 ◽

Vol 118 (20) ◽

pp. 5409-5415 ◽

Cited By ~ 35

Author(s):

Ursula Creutzig ◽

Martin Zimmermann ◽

Jean-Pierre Bourquin ◽

Michael N. Dworzak ◽

Christine von Neuhoff ◽

...

Keyword(s):

Myeloid Leukemia ◽

Independent Predictor ◽

High Dose ◽

Intensive Chemotherapy ◽

Event Free Survival ◽

Core Binding Factor ◽

Free Survival ◽

Binding Factor ◽

High Dose Cytarabine ◽

Pediatric Aml

Abstract Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, plogrank0.047, EFS 84% ± 4% versus 59% ± 7%, plogrank0.001, and CIR 14% ± 4% versus 34% ± 7%, p(gray)0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

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Pediatric-Based Versus Adult Treatment Protocols in Young Adults (18-40 years) with Standard Risk Acute Lymphoblastic Leukemia: The BC Cancer Agency Experience

Blood ◽

10.1182/blood.v126.23.3770.3770 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3770-3770 ◽

Cited By ~ 2

Author(s):

David Simon Kliman ◽

Michael J Barnett ◽

Raewyn Broady ◽

Donna L. Forrest ◽

Alina S. Gerrie ◽

...

Keyword(s):

British Columbia ◽

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Survival Rates ◽

High Dose ◽

Event Free Survival ◽

Free Survival ◽

Small Cohort ◽

Standard Risk

Abstract Introduction In recent decades, overall survival rates for children with acute lymphoblastic leukemia (ALL) have improved dramatically. Unfortunately, older patients have not experienced the same benefit. Recent years have seen investigation into the use of pediatric protocols for younger adults with ALL. Increased toxicity has often limited use to patients 40 years or younger. The Leukemia/Bone Marrow Transplant Program of BC is the referral center for adults with ALL in British Columbia. Approximately 20 patients are newly diagnosed with ALL each year. Until 2008, an adult protocol (known as ALL 89-1) was used in patients over 18 years. Since 2008, pediatric-based chemotherapy has been offered to patients 40 years or younger. We analyzed whether this change altered complete remission (CR), relapse and survival rates. We assessed whether the more intense protocol increased toxicity. Methods A retrospective analysis was performed on patients treated for ALL on a pediatric-based protocol. These protocols (ALL 08-01 and ALL 13-01) were modifications of the Donna Farber Cancer Institute 01-175 protocol. The format included induction with high dose methotrexate, followed by central nervous system (CNS) therapy including cranial irradiation. A single cycle of etoposide and high-dose cytarabine was given. Consolidation and continuation cycles included doxorubicin, asparaginase, vincristine and dexamethasone. Patients were included if they were aged 18-40 years and had standard risk, Philadelphia chromosome negative ALL. Between February 2008 and November 2014, 25 eligible patients were identified. These were compared with the 23 consecutive standard risk patients most recently treated with ALL 89-1. They had been diagnosed between February 2003 and July 2008. Exclusion criteria were age greater than 40 and non-standard risk ALL. Demographic and clinical data were collected on all patients from the Leukemia Program databases. Overall survival (OS) was calculated from time of diagnosis until death. Event free survival (EFS) was calculated from diagnosis until death, induction failure or relapse. Estimation of OS and EFS was performed using the Kaplan-Meier method. Patient characteristics were compared using Chi-squared test or Fisher's exact test. Ethics approval was obtained from the University of British Columbia ethics board. Results The median age of the combined patient group was 24.5 years. There were no statistically significant differences pre-treatment between groups. Combined median follow up was 28.7 months All 25 patients receiving a pediatric protocol achieved a CR, compared to 19 of 22 with the adult protocol. Despite the more intense chemotherapy dosing regimen in the pediatric protocol, there was no increase in hospitalizations, invasive fungal infections or deaths from treatment toxicity (Table 1). There was a trend towards increased thrombotic events in the pediatric-treated group, at 32% versus 9%. These included deep vein thrombosis in 4 patients, pulmonary emboli in 2, and cerebral sinus thrombosis in 2. Relapse occurred in 24% of the pediatric-treated patients and 45% of the adult-treated ones (p=0.215). Allogeneic stem cell transplantation was performed in 4 patients in the former group and 7 in the latter. Nine of these were carried out in CR2 or later, with two patients going into transplant with active disease. Overall survival following transplant was 44%. Two year event free survival was significantly improved in the group treated on the pediatric protocol (Figure 1), at 79% versus 36% (p=0.011). There was a trend towards improved overall survival in this small cohort, at 83% versus 49% (Figure 2). Conclusions A pediatric-based ALL treatment protocol was tolerated in patients up to the age of 40 years. In our centre, this is associated with an increase in EFS, and a trend towards increased OS, even considering the small cohort. We await with interest the results of larger studies investigating the ideal upfront therapy for young patients with ALL. Table 1. Results All Patients N=47 Adult N=22 Pediatric N=25 P Number % Number % Number % CR after induction 44 of 47 94 19 of 22 86 25 of 25 100 .095 Severe infection 20 of 47 43 9 of 22 41 11 of 25 44 .831 Thrombosis 10 of 47 21 2 of 22 9 8 of 25 32 .079 Pancreatitis 2 of 47 4 0 of 22 0 2 of 25 8 .491 Toxicity deaths 3 of 47 6 2 of 22 9 1 of 25 4 .593 Relapse 16 of 47 34 10 of 22 45 6 of 25 24 .215 AlloHSCT 11 of 47 23 7 of 22 32 4 of 25 16 .303 Disclosures No relevant conflicts of interest to declare.

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