scholarly journals The IG/TR Next Generation Marker Screening Developed within Euroclonality-NGS Consortium Is Successful in 94% of Acute Lymphoblastic Leukemia Samples

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2830-2830
Author(s):  
Michaela Kotrova ◽  
Henrik Knecht ◽  
Dietrich Herrmann ◽  
Martin Schwarz ◽  
Karin Olsen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Next Generation ◽  
Multiplex Pcrs ◽  
Number Of Patients ◽  
Support Research ◽  
Higher Sensitivity ◽  
Marker Identification

Abstract Introduction The current gold standard molecular method for minimal residual disease (MRD) assessment is RQ-PCR for detection of leukemia-associated immunoglobulin (IG) and T cell receptor (TR) rearrangements, which must be identified beforehand in the diagnostic material. Conventional screening of IG/TR rearrangements in the diagnostic sample consists of several multiplex PCRs followed by Sanger sequencing. Recently, the EuroClonality-NGS Consortium (www.euroclonalityngs.org, coordinated by AW Langerak) developed a set of assays for next-generation sequencing-based marker identification in lymphoid malignancies (Brüggemann, Haematologica, 2017). We have been using this approach in routine diagnostics since 2016 and herein we provide an overview of markers detected in acute lymphoblastic leukemia (ALL) patients. Material & Methods Between 02/2017 and 06/2018, 471 ALL samples were screened employing the EuroClonality-NGS assay. The assay consists of 5-8 multiplex PCRs, depending on the type of malignancy [IGH-VJ, IGH-DJ, TRB-VJ, TRB-DJ, TRG, TRD, and IGK-VJ-Kde (and intron-Kde) tubes] followed by a 2nd-step PCR in which barcodes and sequencing adaptors are introduced. The resulting libraries were sequenced on the Illumina MiSeq, producing 2×250bp reads, aiming to reach at least 3000 reads per sequencing library. Rearrangements with an abundance ≥ 5% were considered to be leukemia-associated. Out of the 471 investigated samples, 453 were diagnostic (dx) and 18 were relapse (rel) samples. If available, bone marrow samples (BM) were investigated (n=370), otherwise peripheral blood (PB) samples were used (n=101). For B-ALL patients (n=344) all PCRs were performed, whereas for T-ALL (n=127) the IGH-VJ and both IGK tubes were omitted. Results At least one leukemia-associated marker was detected in 244/253 (96%) B-ALL dx BM samples (Fig. 1A), 237 (94%) of patients carried two or more rearrangements. On average we detected 5.1 markers per patient (range 0-10). The majority of patients carried at least one complete IGH (168; 66%), TRG (155; 61%), TRD (154; 61%), or IGK (142; 56%) rearrangement (Fig. 1B). In dx BM T-ALL samples at least one leukemic marker was detected in 88/100 (88%) cases, and in 80 cases (80%) two or more were detected (Fig. 1C). On average 3.6 markers per patient were detected (range 0-10). The majority of patients carried TRG (67; 67%), TRD (65; 65%), or complete TRB (52; 52%) rearrangements (Fig. 1D). In dx PB samples at least 1 marker was detected in 74/75 (98%) B-ALL (on average 5.2 markers per patient), and 23/25 (92%) T-ALL samples (on average 3.7 markers per patient). Out of 18 rel samples (17 BM, 1 PB; 16 B-ALL, 2 T-ALL), 14 (78%) carried at least 1 rearrangement and 13 (72%) at least two rearrangements. On average 3.7 markers per patient were detected. Conclusions The EuroClonality-NGS assays detected at least 1 leukemic marker in 443/471 (94%) patients in our cohort. The number of patients with no marker was higher in the T-ALL cohort (15/127; 12%) compared to the B-ALL cohort (13/344; 4%). Only 3/100 (3%) dx PB samples had no marker detected, which is surprising considering the usually lower leukemic infiltration of PB in B-ALL, but can be attributed to the higher sensitivity of NGS. Besides higher sensitivity, NGS-based marker identification brings along other benefits: the turn-around time is shorter and it is possible to detect multiple markers per tube without laborious cloning, or splitting the multiplex PCRs into singleplex. Overall, EuroClonality-NGS assays have been shown to be robust, sensitive, and routinely applicable in a clinical diagnostic setting. Disclosures Goekbuget: Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding. Brüggemann:PRMA: Consultancy; Pfizer: Speakers Bureau; Roche: Speakers Bureau; Regeneron: Research Funding; Affimed: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy.

scholarly journals Next-Generation Sequencing in Acute Lymphoblastic Leukemia

2019 ◽  
Vol 20 (12) ◽  
pp. 2929 ◽  
Author(s):  
Nicoletta Coccaro ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Giorgina Specchia ◽  
Francesco Albano
Keyword(s):  
Next Generation Sequencing ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Age Of Onset ◽  
Lymphoblastic Leukemia ◽  
Genomic Analysis ◽  
Next Generation ◽  
Acute Leukemias ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for about a quarter of adult acute leukemias, and features different outcomes depending on the age of onset. Improvements in ALL genomic analysis achieved thanks to the implementation of next-generation sequencing (NGS) have led to the recent discovery of several novel molecular entities and to a deeper understanding of the existing ones. The purpose of our review is to report the most recent discoveries obtained by NGS studies for ALL diagnosis, risk stratification, and treatment planning. We also report the first efforts at NGS use for minimal residual disease (MRD) assessment, and early studies on the application of third generation sequencing in cancer research. Lastly, we consider the need for the integration of NGS analyses in clinical practice for genomic patients profiling from the personalized medicine perspective.

scholarly journals AVA4746, an Orally Available, Clinical Grade Antagonist of Integrin Alpha 4, Sensitizes Pre-B Cell Acute Lymphoblastic Leukemia to Chemotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2765-2765 ◽  
Author(s):  
Yongsheng Ruan ◽  
Eun Ji Gang ◽  
Hye-Na Kim ◽  
Chintan Parekh ◽  
Hisham Abdel-Azim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Metabolic Activity ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Drug Resistant ◽  
Support Research

Abstract Background. Even though remarkable progress has been made in the treatment of childhood acute lymphoblastic leukemia (ALL), salvage of relapse patients remains a challenge. The role of the bone marrow (BM) microenvironment is critical to protect leukemia cells from chemotherapy. The BM microenvironment promotes cell adhesion-mediated drug resistance (CAM-DR) in ALL.We and others have shown that the adhesion molecule integrin α4, referred to hereafter as α4, mediates drug resistance of B-ALL. In our previous studies, we showed that both α4 blockade by natalizumab and inhibition by the small molecule α4 antagonist TBC3486 can sensitize relapsed ALL cells to chemotherapy. However, no α4 targeting therapy is currently clinically available to treat leukemia. Here, we preclinically evaluate a novel non-peptidic small molecule antagonist, AVA4746, which has been safely used in clinical studies, as a potential new approach to combat drug resistant ALL. Method. Six refractory or relapsed primary pre-B ALL cases were used for in vitro studies. Viability was assessed by trypan blue counts or annexin V/7AAD flow cytometric analysis and metabolic activity was evaluated by Cytoscan WST-1 assay. For in vivo evaluation a NOD/SCID IL2Rγ-/- xenograft model of primary pre-B ALL (LAX7R) was used.AVA4746 (15mg/kg) was administered by oral gavage twice a day continuously for 14 days, and vincristine, dexamethasone, L-asparaginase (VDL) was given intraperitoneally (weekly) for 4 weeks. Overall survival was determined by Kaplan-Meier Survival analysis. Results. AVA4746 caused a significant decrease in mean fluorescence intensity (MFI) of α4 expression in six out of six ALL cases at doses of both 5μM and 25μM after 24 hours and 96 hours compared to DMSO control. Interestingly, decreased protein expression of α4 was also observed by Western Blot analysis all six ALL cases. We tested next in two cases (LAX53, ICN13), if AVA4746 de-adheres ALL cells from its counter receptor VCAM-1. The percentages of adherence after treatment with AVA4746 (25μM) were significantly lower than after DMSO treatment (10.3%±4.9% vs. 99.9%±7.6%, p= 0.00007 for LAX7R; 8.1%±1.0% vs. 100.1%±13.6%, p= 0.0003 for LAX53; 9.0%±1.6% vs. 100.0%±14.0%, p=0.0004 for ICN13). AVA4746 was not associated with apoptosis in vitro alone or in combination with chemotherapy (VDL). Metabolic activity as assessed by WST-1 assay was markedly decreased by AVA4746 in two of two ALL cases. AVA4746 also decreased ALL proliferation in two out of two ALL samples tested. In vivo, AVA4746 in combination with VDL chemotherapy treatment led to significant prolongation of overall survival (n=6) compared with the VDL only treated group (n=6) (MST= 78.5 days vs MST= 68 days; P<0.05). There was no significant difference in survival between the PBS control group (n=5) and the AVA4746 mono-treatment group (n=5) (MST=38days vs MST= 38days). Conclusion. We have identified α4 as a central adhesion molecule in CAM-DR of ALL and have shown that AVA-4746, an orally available and specific α4 antagonist, which has been safely used in clinical studies, downregulates α4 in primary ALL and functionally de-adheres them from VCAM-1. Critically, we demonstrated that inhibition of α4 in combination with standard chemotherapy can prolong the survival of NSG mice bearing pre-B ALL. These data support further study of inhibition of α4 using AVA4746 as a novel strategy to treat drug resistant B lineage ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties. Kim:Antisense Therapeutics Ltd: Patents & Royalties.

scholarly journals Acute lymphoblastic leukemia in adults

2011 ◽  
Vol 3 (2s) ◽  
pp. 1 ◽  
Author(s):  
Josep-Maria Ribera
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
New Drugs ◽  
Therapeutic Modality ◽  
Neoplastic Disease ◽  
Hematopoietic Stem ◽  
Therapeutic Modalities ◽  
Number Of Patients

Acute lymphoblastic leukemia (ALL) is the most frequent neoplastic disease in children, being a rare disease in adults. Many of the advances in pediatric ALL have been through modifications in the doses and schedules of available agents as opposed to the introduction of new compounds. In recent years some improvements in the outcome of ALL in adults have occurred. Application of pediatric regimens to young and middle-aged adults shows promise to improve outcome. Advances in the supportive care of patients undergoing allogeneic stem cell transplantation (SCT), the use of alternative sources of hematopoietic stem cells and the use of reduced-intensity conditioning regimens will expand the number of patients who can benefit from this therapeutic modality. The evaluation of minimal residual disease will further stratify risk classification and redefine the role of therapeutic modalities such as SCT or biologic agents. New drugs such as thyrosin kinase inhibitors or monoclonal antibodies have led to incremental improvements in outcome. Advances in the genetic and epigenetic mechanisms of the disease provide hope that targeted therapies can more effectively treat the disease with less toxicity.

scholarly journals Health-Related Quality of Life in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia and Minimal Residual Disease Treated with Blinatumomab

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1377-1377 ◽  
Author(s):  
Ralf C Bargou ◽  
Gerhard Zugmaier ◽  
Massimiliano Bonifacio ◽  
Carlos Graux ◽  
Christoph Faul ◽  
...  
Keyword(s):  
Health Status ◽  
Global Health ◽  
B Cell ◽  
Social Functioning ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Global Health Status ◽  
Cell Precursor ◽  
Support Research

Abstract Background: Positive minimal residual disease (MRD) is an established prognostic marker for hematologic relapse, negative hematopoietic stem cell transplantation (HSCT) outcome, and mortality in adults with B-cell precursor acute lymphoblastic leukemia (ALL; Gökbuget N, et al. Blood. 2012;120:1868-1876). In the open-label, single-arm phase 2 BLAST study (N=116; ClinicalTrials.gov, NCT01207388), treatment with blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to residual CD19+ blast cells, led to complete MRD response in 88 of 113 (78%) patients after cycle 1 (Gökbuget N, et al. Blood. 2018;131:1522-1531). Median overall survival was 36.5 months. Among patients with Philadelphia chromosome-negative B-cell ALL in complete MRD remission, relapse-free survival was 54% at 18months. In this analysis of the BLAST study, we assessed the health-related quality of life (HRQoL) of patients during and after treatment with blinatumomab. Methods: Eligible patients (≥18 years) had B-cell precursor ALL in first or later hematologic complete remission and persistent or recurrent MRD ≥10-3 after ≥3 blocks of intensive chemotherapy. Blinatumomab 15 μg/m2/day was administered by continuous intravenous (cIV) infusion for 4 weeks, followed by a 2-week infusion-free interval, for up to 4 cycles. Patients could receive HSCT any time after cycle 1. HRQoL was assessed using the EORTC QLQ-C30 Questionnaire at baseline, on day 29 of each treatment cycle, at the safety follow-up visit (30 days after end of treatment), and at the efficacy follow-up visits (3, 6, 9, 12, 18, and 24 months after treatment start). The questionnaire included 1 global health status scale, 5 functioning scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single-symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For global health status and functioning scales, a higher score indicates better HRQoL; for symptom scales/items, a lower score indicates better HRQoL. A 10-point change is often viewed as the minimum clinically important difference (MID) in EORTC QLQ-C30 (Zikos E, et al. EORTC, 2016). In this analysis, the mean (SD) and the mean (SD) change from baseline to end of cycle 1 of the scores for each scale/item was summarized at each scheduled assessment during and after blinatumomab treatment. Results: In total, 89 patients had a nonmissing baseline value and a nonmissing value of any scale on day 29 of cycle 1, and thus were evaluable for HRQoL. The patient-reported global health status and functioning scale scores were stable over time during and after blinatumomab treatment (Figure 1). Symptom-scale and single-symptom scores were similarly stable during and after treatment (not shown). Mean (SD) changes from baseline to end of cycle 1 in global health status and in physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning were 2.5 (18.5), 0.3 (12.5), -4.0 (30.0), 4.2 (20.5), -1.7 (16.2), and 10.4 (31.8), respectively (Figure 2). These results show that, after 1 cycle of blinatumomab, the change in HRQoL was minimal for most scales, with potential clinically meaningful improvements in social functioning. Similar minimal changes were observed for all symptom scales/items (not shown). Conclusions: In this population of patients with B-cell precursor ALL and MRD successfully treated with blinatumomab 15 μg/m2/day cIV for up to 4 cycles, HRQoL was maintained during and after blinatumomab treatment, which is an important result considering the potential HRQoL impact of standard chemotherapy. Disclosures Zugmaier: Amgen Inc.: Consultancy, Employment, Patents & Royalties: 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140227272, 20140228316, 20130323247, 20130287774, 20130287778, 20110262440, 20100112603, 7700299, 20070037228. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Topp:Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Tran:Amgen Inc.: Employment. Zhang:Amgen Inc.: Employment, Equity Ownership. Goekbuget:Kite / Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Other: Travel support, Research Funding; Pfizer: Consultancy, Other: Travel support, Research Funding; Amgen: Consultancy, Other: Travel support, Research Funding.

Minimal Residual Disease Detected Prior to Transplantation Is Associated with Adverse Outcome in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3246-3246
Author(s):  
Jennifer H Foster ◽  
Anne Woolfrey ◽  
Brent Wood ◽  
Blythe Thomson
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Color Flow ◽  
Relapse Risk ◽  
Risk Of Death ◽  
Number Of Patients ◽  
Minimal Residual

Abstract Background: Acute lymphoblastic leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however for those patients who relapse, hematopoeitic stem cell transplantation (HSCT) offers a reasonable chance of cure. Minimal residual disease (MRD) detection by Multiparametric Flow Cytometery (MPF) is being used for risk adapted treatment decisions in many ALL trials. We present a series of 31 pediatric ALL patients who had morphologic and MPF evaluation of disease burden prior to ablative HSCT. Methods: Thirty one patients were treated at Children’s Hospital and Regional Medical Center, Seattle, WA for relapsed or very high risk ALL, were in complete morphologic remission, and received an ablative HSCT from May 2006-May 2008. Twelve patients were in second or third complete remission (CR) and 19 were in first CR. Eleven patients received a matched related donor, 20 patients received a unrelated donor graft. All patients underwent marrow evaluation including morphology and MPF within four weeks of their transplant date. The MPF was done by 7 or 9 color flow cytometry using the following reagents for B lineage: CD10, CD19, CD20, CD34, CD38, CD58 and CD45 and for T lineage: CD2, CD3, CD4, CD5, CD7, CD8, CD34, CD56, and CD45. Transplant regimens were total body irradiation-based (1320 cGy) with either cyclophosphamide (n=24) or fludarabine (n=6). MRD+ was any detectable leukemia >0.01% of cells. All patients were in morphologic remission (< 5% blasts) at time of transplant. Events were defined as relapse or deaths. Results: 21 patients were MRD-, 10 were MRD+. The 2 year event free survival (EFS) for the entire group was 56% (+/−22%). The EFS at 20 months for those patients in CR1 and CR2/3 were 62% (+/−32%) and 40% (+/−32%), respectively. EFS, relapse risk and non relapse mortality was analyzed with respect to MRD status: MRD+ (n=10) MRD- (n=21) p value EFS 36% (+/−32%) 68% (+/−26%) 0.037 Relapse Risk 48% (+/−36%) 13% (+/−16%) 0.036 Non-relapse Mortality 30% (+/−36%) 23% (+/−26%) 0.45 Discussion: We present a single institution series of patients treated for high risk or relapsed ALL who underwent disease evaluation prior to HSCT with MPF. With the small number of patients evaluated, it appears that any amount of disease detected by MPF was an adverse risk factor for recurrence. Those patients who were MRD+ experienced a higher risk of death from relapse, however, experienced no difference in non-relapse mortality. Resistant disease as detected by MRD analysis at time of transplant is a marker for poor outcome.

Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report From Children's Oncology Group (COG) Study AALL0232

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1440-1440 ◽  
Author(s):  
Michael J. Borowitz ◽  
Brent L. Wood ◽  
Meenakshi Devidas ◽  
Mignon L Loh ◽  
Elizabeth A. Raetz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Oncology Group ◽  
Children And Young Adults ◽  
Minimal Residual

Abstract Abstract 1440 Improved Post-Induction Chemotherapy Does Not Abrogate Prognostic Significance of Minimal Residual Disease (MRD) for Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (ALL). A Report from Children's Oncology Group (COG) Study AALL0232. Minimal residual disease is one of the strongest prognostic factors in pediatric ALL. COG AALL0232 was a phase 3 randomized trial for patients 1–30 years old with newly diagnosed NCI HR B precursor ALL that used a 2×2 factorial study design comparing dexamethasone (DEX) versus(vs.) prednisone(PRED) during induction, and high dose methotrexate (HD-MTX) vs. Capizzi methotrexate (C-MTX) during interim maintenance 1(IM-1). We previously reported improved event-free survival (EFS) for patients receiving HD-MTX vs. C-MTX (J Clin Oncol 29: 6s, 2011) and for DEX vs. PRED among patients <10 years old randomized to HD-MTX(J Clin Oncol 29: 586s,2011). MRD was measured by 6 color flow cytometry in two central labs (MJB and BLW) to a level of sensitivity of 0.01% at end induction. Patients with >=0.1% MRD at end induction, as well as patients with morphologic slow early response or specific adverse genetic features received intensified therapy including IM-2 and a second delayed intensification, and then had MRD determined at end consolidation, (about 13 weeks post diagnosis). End induction MRD > =0.01% was highly predictive of inferior outcome, though patients with 0.1–1% MRD who received intensive therapy had very low rates of early relapse and a much higher rate of late relapse. 5 year EFS for end-induction MRD positive (>=0.01%) patients was 63±5% vs. 86±2% for MRD negative patients. However, patients who were MRD positive at end induction who became negative by end consolidation had improved 5y EFS of 79±9%(n=136) compared to 52±14% for those who remained MRD positive(n=52) (p=.0012). Both end induction MRD positive and negative patients benefitted from HD-MTX vs. C-MTX, though the effect was small and did not reach statistical significance for MRD positive patients. By contrast, end-induction MRD was highly predictive of outcome for patients receiving either HD-MTX or C-MTX. 5 y EFS as a function of MRD status and IM regimen.End induction MRDCapizziHDMTXP value<.01%84 ± 3%88 ± 2%.04>.01%59 ± 6%67 ± 7%.12P value<.0001<.0001 End induction MRD negative patients <10y receiving DEX had better outcome than those getting PRED (5 y EFS 92±3% vs. 87±4% P=.027) while MRD positive patients or those>10y showed no difference. However, DEX patients <10y if anything had a slightly higher rate of end induction MRD positivity than those given PRED (22% vs. 17%, p=.073). In multivariate analysis, end consolidation MRD was the most powerful prognostic factor for the small subset of patients in whom this was assessed. Excluding this, end induction MRD was the most significant variable; age, white blood cell count, day 15 marrow morphology and HD-MTX vs. C-MTX were also significant. We conclude that MRD remains the most powerful prognostic factor even in the context of improved therapy. Additionally, for those patients who were MRD positive at end induction, achieving MRD negative status by end consolidation improved outcome significantly. The higher frequency of MRD in younger patients receiving DEX calls into question the validity of using end induction MRD as a surrogate for outcome when testing novel interventions during induction therapy. Disclosures: Borowitz: BD Biosciences: Research Funding. Wood:BD Biosciences: Research Funding.

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