scholarly journals Biosimulation Using the Cellworks Computational Omics Biology Model (CBM)-Based Assessment of Cytarabine (ARA-C) and Anthracycline Response and Novel Biomarker Response Criteria for the Addition of Etoposide (VP16) in Acute Myeloid Leukemia (AML)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1299-1299
Author(s):  
Michael Castro ◽  
Scott C Howard ◽  
Ansu Kumar ◽  
Vivek Patil ◽  
Swati Khandelwal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Specific Protein ◽  
Copy Number Variations ◽  
Protein Network ◽  
Patient Specific ◽  
Advisory Committees ◽  
Biomarker Response ◽  
Acute Myeloid

Abstract Background: Genomic heterogeneity in leukemic blasts characterizes Acute Myeloid Leukemia (AML) patients and is associated to variable drug response. However, use of genomics to guide therapy has generally been restricted to a single-gene approach, which rarely has sufficient predictive power to be clinically useful. Comprehensive DNA sequencing and biosimulation of the Computational Omics Biology Model (CBM) provide the opportunity and means of predicting treatment outcome in advance of treatment. Methods: The Cellworks CBM is a computational multi-omic biology software model created using artificial intelligence heuristics and literature sourced from PubMed, to generate a patient-specific protein network map. The CBM permits mapping of biological pathways associated with tumorigenesis and drug resistance using mathematical principles to yield a virtual tumor model that can be used in biosimulation. Aberration and copy number variations from each case served as input to the CBM to generate individual patient-specific protein network maps. We used the Cellworks Biosimulation Platform to identify novel genomic biomarkers associated with response among AML patients treated with Cytarabine (ARA-C) + idarubicin or daunorubicin (anthracycline) with or without Etoposide (VP16). 539 AML patients were selected for this study based largely on genomic data published in TCGA and PubMed: ARA-C + daunorubicin [N=111, 92 responders (R) & 19 non-responders (NR)]ARA-C + idarubicin [N=109, 94 R & 15 NR]ARA-C + daunorubicin + VP16 [N=6, 4 R & 2 NR]ARA-C + idarubicin + VP16 [N=313, 261 R & 52 NR] Drug impact on individual disease networks was simulated to determine efficacy value by measuring the effect of chemotherapy on the cell growth score, a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. The mechanism of action of each drug was used to map its biological consequences to each patient's cancer genome to predict treatment response. Results: Biosimulation of ARA-C + anthracycline with and without VP16 identified biomarkers responsible for therapy response. Additionally, the Cellworks Biosimulation Platform identified novel drug combinations for NR to these standard combinations. There were 186/220 patients treated with ARA-C + anthracycline that had clinical responses. Major biomarkers predictive of response included: IDH2 mut, TOPBP1 del, ATR del, NPM1 mut, IDH1 mut, XRCC2 del, CDK5 del, AKR1B1 del and other genes (Table 1). The frequency of these genes was significantly higher (exact binomial: p-value < 0.0001) in R (N=186) vs. NR (N=34). Notably, 7/34 NR to the two-drug combination had favorable biomarkers for VP16 response, which included RAD52 del, FANCD2 del, STAG2 mut, MPO amp, and NHEJ del. On the other hand, among 265 R treated with triplet therapy (ARA-C + anthracycline + VP16), 30 patients were unlikely to have derived incremental benefit from the addition of VP16. In these patients, the biosimulation predicted that they would have benefited equally from doublet therapy (ARA-C + anthracycline without VP16). In this subgroup of R, ARID1A del, FLT3-ITD mut, GSTA1 amp, KEAP1 del, or RNF1 del generated resistance to VP16 in the biosimulation. Among 54 NR to triplet therapy, 40/54 had genomic alterations predicting a benefit from JQ1, BRD2/4 inhibitors, including KMT2C del, FLT3 GOF, NPM1 del, DNMT3A LOF, and TP53 del, while 12 patients had 5q del highlighting a potential benefit from lenalidomide. Altogether, 89/539 (16.5%) could have been managed with a potentially superior treatment approach based on the biosimulation by either adding or omitting VP16 or being treated with an alternative therapy. Conclusions: Cellworks Biosimulation Platform applied to the patient-specific CBM identifies novel biomarkers of response and can be employed to determine the optimal therapy for AML patients. This study highlights patients for whom triplet therapy promises potentially superior benefit, others who would benefit equally from doublet therapy without VP16, and others unlikely to respond to standard or triplet therapy for whom an alternative personalized approach might offer better outcomes. In AML, biosimulation offers the possibility to tailor the chemotherapy regimen to each patient to improve disease control and minimize toxicity. Figure 1 Figure 1. Disclosures Castro: Caris Life Sciences Inc.: Consultancy; Guardant Health Inc.: Speakers Bureau; Bugworks: Consultancy; Cellworks Group Inc.: Current Employment; Omicure Inc: Consultancy; Exact sciences Inc.: Consultancy. Howard: Servier: Consultancy; Cellworks Group Inc.: Consultancy; Sanofi: Consultancy, Other: Speaker fees. Kumar: Cellworks Group Inc.: Current Employment. Patil: Cellworks Group Inc.: Current Employment. Khandelwal: Cellworks Group Inc.: Current Employment. Watson: BioAi Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; AlloVir: Consultancy, Membership on an entity's Board of Directors or advisory committees; CellMax Life: Consultancy, Other: Advisor; Cellworks Group Inc.: Consultancy, Other: Advisor. Kapoor: Cellworks Group Inc.: Current Employment. Kumari: Cellworks Group Inc.: Current Employment. Prasad: Cellworks Group Inc.: Current Employment. Gupta: Cellworks Group Inc.: Current Employment. Lunkad: Cellworks Group Inc.: Current Employment. Mitra: Cellworks Group Inc.: Current Employment. G: Cellworks Group Inc.: Current Employment. Kumar: Cellworks Group Inc.: Current Employment. Choudhury: Cellworks Group Inc.: Current Employment. Kulkarni: Cellworks Group Inc.: Current Employment. Choudhary: Cellworks Group Inc.: Current Employment. Prakash: Cellworks Group Inc.: Current Employment. Husain: Cellworks Group Inc.: Current Employment. Ghosh: Cellworks Group Inc.: Current Employment. Narvekar: Cellworks Group Inc.: Current Employment. Amara: Cellworks Group Inc.: Current Employment. Yuvavani: Cellworks Group Inc.: Current Employment. Patel: Cellworks Group Inc.: Current Employment. Macpherson: Cellworks Group Inc.: Current Employment. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings.

scholarly journals Biosimulation Using the Cellworks Computational Omics Biology Model (CBM) Identifies Novel Biomarkers to Inform Mitoxantrone, Etoposide, and Cytarabine (MEC)-Based Combination Therapy in Refractory & Relapsed Acute Myeloid Leukemia (AML) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4453-4453
Author(s):  
Guido Marcucci ◽  
Ansu Kumar ◽  
Michael Castro ◽  
Himanshu Grover ◽  
Vivek Patil ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Disease Control ◽  
Myeloid Leukemia ◽  
Intensive Therapy ◽  
Predictive Biomarkers ◽  
Specific Protein ◽  
Copy Number Variations ◽  
Protein Network ◽  
Patient Specific ◽  
Acute Myeloid

Abstract Background: The optimal treatment strategy for managing Acute Myeloid Leukemia (AML) and the use of reliable and predictive biomarkers to guide selection of cytotoxic chemotherapy regimens among patients with diverse genomic profiles remain unmet needs in the clinic. The combination of MEC [mitoxantrone (MIT), etoposide (VP16), and cytarabine (ARA-C)] is a commonly used regimen for relapsed or refractory AML patients. Unfortunately, many patients do not respond to MEC, and which of the three drug agents matters most for each individual patient is not known. Predictors of response are needed urgently. Methods: The Computational Omics Biology Model (CBM) is a computational multi-omic biology software model created using artificial intelligence heuristics and literature sourced from PubMed to generate a patient-specific protein network map. The aberration and copy number variations from individual cases served as input into the CBM. Disease-biomarkers unique to each patient were identified within patient-specific protein network maps. Biosimulations were conducted on the Cellworks Biosimulation Platform by measuring the effect of chemotherapy on a cell growth score comprised of a composite of cell proliferation, viability, apoptosis, metastasis, and other cancer hallmarks. Biosimulation of drugs was conducted by mapping the interaction of various drug combinations with the patient's genomic and pathway alterations based on signaling pathway mechanisms and their phenotypic consequences. The Cellworks Biosimulation Platform identified unique chromosomal signatures that permit a stratification of patients that are most likely to respond to MIT, VP16, or ARA-C as well as their combinations. 65 AML patients were selected for this study largely based on genomic data published in TCGA and PubMed: ARA-C [N=12, 7 responders (R) & 5 non-responders (NR)]ARA-C + MIT [N=30, 29 R & 1 NR]ARA-C + MIT + VP16 [N=23, 12 R & 11 NR] Results: Of the12 patients treated with ARA-C alone, 5 were predicted to be NR and 7 were predicted to be R. Of the 5 NR, 4 had 5q del which resulted in loss of APC, CSNK1A1 and SLC22A4 (nucleoside carrier) forming the non-response biomarkers for ARA-C. Notably, the biosimulation predicted lenalidomide to be beneficial for these patients. Out of 7 R, 4 patients also had 5q del, but were predicted to be R because of co-occurring aberrations involving CLSPN del, DHODH del, MSH2 del, EP300 del, CREBBP del, MSH6 Del, and RRM2 del. These genes were exclusively present in ARA-C responders. Of 53 patients who received ARA-C + VP16 + MIT or ARA-C + MIT, 41 patients were predicted to be R and 12 patients were predicted to be NR. The genomic aberrations predicted by biosimulation to be associated with response to this regimen include: NPM1-mut, TET2-mut, IDH1-mut, IDH2-mut, RAD17-del, NRAS-mut (Table 1). Notably, CBM predicted 19 of the 41 R had no genomic biomarkers of response to VP16 or MIT, suggesting these patients might have benefited equally from ARA-C alone with less toxicity and cost. Finally, 11/65 patients were predicted NR to MEC treatment. In the biosimulation, treatment failure was associated with high aberration frequencies of KMT2C-mut/del, FLT3 mut, TWIST1 del, LIMK1 del, SNAI2 amp, FNTA amp, and KAT6A amp. Of note, these genomic markers suggested a likelihood of benefit from other therapies, including vincristine, JQ1 and rigosertib. Conclusions: The Cellworks Biosimulation Platform identified novel polygenic biomarkers of response that can be employed to determine the optimal therapy for relapsed AML patients. Biosimulation permits avoidance of cytotoxic drugs with little chance of efficacy and reveals vulnerabilities in each patient's cancer that can be exploited to improve disease control. In AML, biosimulation promises to improve intensive therapy regimens by tailoring chemotherapy to optimize disease control and minimize toxicity. Figure 1 Figure 1. Disclosures Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Kumar: Cellworks Group Inc.: Current Employment. Castro: Cellworks Group Inc.: Current Employment; Omicure Inc: Consultancy; Caris Life Sciences Inc.: Consultancy; Exact sciences Inc.: Consultancy; Bugworks: Consultancy; Guardant Health Inc.: Speakers Bureau. Grover: Cellworks Group Inc.: Current Employment. Patil: Cellworks Group Inc.: Current Employment. Alam: Cellworks Group Inc.: Current Employment. Azam: Cellworks Group Inc.: Current Employment. Mohapatra: Cellworks Group Inc.: Current Employment. Tyagi: Cellworks Group Inc.: Current Employment. Kumari: Cellworks Group Inc.: Current Employment. Prasad: Cellworks Group Inc.: Current Employment. Nair: Cellworks Group Inc.: Current Employment. Lunkad: Cellworks Group Inc.: Current Employment. Joseph: Cellworks Group Inc.: Current Employment. G: Cellworks Group Inc.: Current Employment. Chauhan: Cellworks Group Inc.: Current Employment. Basu: Cellworks Group Inc.: Current Employment. Behura: Cellworks Group Inc.: Current Employment. Ghosh: Cellworks Group Inc.: Current Employment. Husain: Cellworks Group Inc.: Current Employment. Mandal: Cellworks Group Inc.: Current Employment. Raman: Cellworks Group Inc.: Current Employment. Patel: Cellworks Group Inc.: Current Employment. Mundkur: Cellworks Group Inc: Current Employment. Christie: Cellworks Group Inc.: Current Employment. Macpherson: Cellworks Group Inc.: Current Employment. Howard: Servier: Consultancy; Cellworks Group Inc.: Consultancy; Sanofi: Consultancy, Other: Speaker fees.

scholarly journals Donor Cell Acute Myeloid Leukemia after Transplant for Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5697-5697
Author(s):  
Lacey S. Williams ◽  
Catherine E. Lai
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Donor Cell ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Donor Cell Leukemia ◽  
Acute Myeloid

Donor cell leukemia is postulated to account for up to 5% of all leukemia "relapses" after hematopoietic stem cell transplant (SCT), though in many cases this is the first leukemia diagnosis for the patient if their transplant was for non-leukemia primary diseases. The rarity of the condition and heterogeneity of disease create challenges in diagnosis and management. In the present case, donor cell leukemia (DCL) developed in a 68-year-old female after allogeneic SCT 18 years earlier for follicular lymphoma. Only one other case of DCL after transplantation for follicular lymphoma has been reported (Boulton-Jones et al., Bone Marrow Transplantation, 2005). Furthermore, this case is atypical in that the presentation occurred many years after transplantation, since very few cases of DCL occur more than 15 years after original transplant. Case In 1993, the patient was diagnosed with stage IIIA follicular lymphoma at age 50. She achieved a complete remission with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) for 4 years. She relapsed in 1998 and received treatment with fludarabine and mitoxantrone. In 1999, she enrolled in a toxitumomab clinical trial (NCT00268203) but discontinued therapy secondary to side effects. Due to persistent disease, she proceeded with SCT and received EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) prior to allogeneic SCT from her brother in 2000 (6/6 HLA match), augmented with TH2 cells. She received graft versus host disease (GVHD) prophylaxis with cyclosporine, however her post transplant course was complicated by engraftment syndrome and gastrointestinal and skin GVHD. In 2019, she presented to hematology for evaluation of worsening chronic neutropenia and thrombocytopenia persistent for three years, noted during work-up for symptomatic cholelithiasis. Bone marrow biopsy revealed acute myeloid leukemia (AML) with a hypocellular marrow with 30% blasts and myelodysplasia related changes. Her cytogenetics showed 46XY, +1, der(1;7)(q10;p10)/47,sl,+8/46,XY. FISH analyses demonstrated deletion 7q31 D7S486 locus in 156/200 cells (78%). NGS panel showed IDH1 (VAF16%) and U2AF1 (VAF 26%) mutations. Based on cytogenetics and chimerism studies showing 100% donor, the patient was diagnosed with donor-derived AML secondary to allogeneic SCT from her brother. The brother currently has no known hematologic problems. The patient was treated with CPX-351 (liposomal cytarabine and daunorubicin) and achieved a complete remission, followed by consolidation with CPX-351. Given her complex cytogenetics and poor prognosis, the patient proceeded to non-myeloablative haploidentical peripheral blood SCT from her son, with post-transplant cyclophosphamide. She subsequently had complications of neutropenic fever and C. dificile colitis, with progressive colitis leading to her death on day 22 after SCT. Discussion Though cytogenetic and molecular studies along with functional status assist clinicians in treatment decisions for DCL patients, the benefits and risks of treatment remain difficult to balance for this unique subset of leukemia. Of patients that achieve remission for greater than 18 months, many undergo second allogeneic SCT, however a similar number of patients have remissions of at least 18 months treated with chemotherapy alone (Wiseman, Biology of Blood and Bone Marrow Transplantation, 2011). In 15 reported cases that went to SCT, approximately 50% lived longer than 12 months after their DCL diagnosis. Second allogeneic SCT is often favored after initial remission in patients with good performance status due to high risk for relapse. This case illustrates the challenge in management of donor cell leukemia, a rather rare entity with very few cases in the literature developing greater than 15 years after transplant. Limited robust evidence favoring a particular treatment supports the need for further prospective studies. Disclosures Lai: Agios: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Astellas: Speakers Bureau.

scholarly journals Phase I Study of Ixazomib with Conventional Chemotherapy in the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Geoffrey Fell ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Remission Rate ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged >60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

scholarly journals Epigenetic Activation of the pH Regulator MCT4 in Acute Myeloid Leukemia Exploits a Fundamental Metabolic Process of Enhancing Cell Growth through Proton Shifting

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3765-3765
Author(s):  
Cheuk-Him Man ◽  
David T. Scadden ◽  
Francois Mercier ◽  
Nian Liu ◽  
Wentao Dong ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Growth ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Monocarboxylate Transporter ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Equity Ownership ◽  
Acute Myeloid

Acute myeloid leukemia (AML) cells exhibit metabolic alterations that may provide therapeutic targets not necessarily evident in the cancer cell genome. Among the metabolic features we noted in AML compared with normal hematopoietic stem and progenitors (HSPC) was a strikingly consistent alkaline intracellular pH (pHi). Among candidate proton regulators, monocarboxylate transporter 4 (MCT4) mRNA and protein were differentially increased in multiple human and mouse AML cell lines and primary AML cells. MCT4 is a plasma membrane H+and lactate co-transporter whose activity necessarily shifts protons extracellularly as intracellular lactate is extruded. MCT4 activity is increased when overexpressed or with increased intracellular lactate generated by glycolysis in the setting of nutrient abundance. With increased MCT4 activity, extracellular lactate and protons will increase causing extracellular acidification while alkalinizing the intracellular compartment. MCT4-knockout (MCT4-KO) of mouse and human AMLdid not induce compensatory MCT1 expression, reduced pHi, suppressed proliferation and improved animal survival. Growth reduction was experimentally defined to be due to intracellular acidification rather than lactate accumulation by independent modulation of those parameters. MCT4-KOmetabolic profiling demonstrated decreased ATP/ADP and increased NADP+/NADPH suggesting suppression of glycolysis and the pentose phosphate pathway (PPP) that was confirmed by stable isotopic carbon flux analyses. Notably,the enzymatic activity of purified gatekeeper enzymes, hexokinase 1 (HK1), pyruvate kinase M2 isoform (PKM2) and glucose-6-phosphate dehydrogenase (G6PDH) was sensitive to pH with increased activity at the leukemic pHi (pH 7.6) compared to normal pHi (pH 7.3). Evaluating MCT4 transcriptional regulation, we defined that activating histonemarks, H3K27ac and H3K4me3, were enriched at the MCT4 promoter region as were transcriptional regulators MLL1 and Brd4 by ChIP in AML compared with normal cells. Pharmacologic inhibition of Brd4 suppressed Brd4 and H3K27ac enrichment and MCT4 expression in AML and reduced leukemic cell growth. To determine whether MCT4 based pHi changes were sufficient to increase cell proliferation, we overexpressed MCT4 in normal HSPC and demonstrated in vivo increases in growth in conjunction with pHi alkalization. Some other cell types also were increased in their growth kinetics by MCT4 overexpression and pHi increase. Therefore, proton shifting may be a means by which cells respond to nutrient abundance, co-transporting lactate and protons out of the cell, increasing the activity of enzymes that enhance PPP and glycolysis for biomass generation. Epigenetic changes in AML appear to exploit that process by increasing MCT4 expression to enforce proton exclusion thereby gaining a growth advantage without dependence on signaling pathways. Inhibiting MCT4 and intracellular alkalization may diminish the ability of AML to outcompete normal hematopoiesis. Figure Disclosures Scadden: Clear Creek Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Sponsored research; Editas Medicine: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bone Therapeutics: Consultancy; Fog Pharma: Consultancy; Red Oak Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; LifeVaultBio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Equity Ownership.

scholarly journals EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Sebastian Stasik ◽  
Jan Moritz Middeke ◽  
Michael Kramer ◽  
Christoph Rollig ◽  
Alwin Krämer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutational Status ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

scholarly journals Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 338-338
Author(s):  
Bradstock Kenneth ◽  
Emma Link ◽  
Juliana Di Iulio ◽  
Jeff Szer ◽  
Paula Marlton ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Consolidation Therapy ◽  
Advisory Committees ◽  
Free Survival ◽  
Acute Myeloid

Abstract Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p<0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Expression Of Aldehyde Dehydrogenase Reflected Diverse Stem Cell Properties In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1344-1344
Author(s):  
Van T. Hoang ◽  
Eike C. Buss ◽  
Isabel Hoffmann ◽  
Abraham Zepeda-Moreno ◽  
Natalia Baran ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Clinical Study ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Aldh Activity ◽  
Advisory Committees ◽  
Low Frequencies ◽  
Acute Myeloid

Abstract Separation of leukemic stem cells (LSC) and residual hematopoietic stem cells (HSC) from the same individual patient with acute myeloid leukemia (AML) is essential for a proper understanding of the leukemic driving mechanisms. We have studied the role of aldehyde dehydrogenase (ALDH) for this purpose and have defined the functional properties of ALDHbright cells in specific subgroups of AML. We have examined the ALDH activity by flow cytometry in bone marrow samples (BM) from 14 healthy donors and 73 patients with de novo AML. The median frequency of cells with high ALDH activity (ALDHbright cells) in the healthy subjects was 1.92% with a range from 0.58 to 3.16%. For patients with AML, the median number of ALDHbright cells was 0.25% with a broad range from 0.004 to 33.57%. Whereas the majority of patients with AML (n = 56) had low frequencies of ALDHbright cells (median 0.11%; range 0.004 – 1.77%; defined as ALDH-low AML), 17 patients had relatively numerous ALDHbright cells (median 9.01; range 3.54 – 33.57%; defined as ALDH-numerous AML). In both groups, ALDHbright cell populations were highly enriched for CD34+CD38- cells. The ALDHbright cells derived from ALDH-low AML did not contain chromosomal and molecular aberrations characteristic of the original leukemia, and were able to induce multi-lineage hematopoiesis in NSG mouse models. Thus, genetically and functionally normal HSC could be successfully isolated in the ALDHbright subset, whereas LSC were enriched in ALDHdimCD34+CD38- subset for patients with ALDH-low AML. For 17 patients with ALDH-numerous AML, the ALDHbright subset was consistently contaminated with LSC. In clinical follow-ups, patients with ALDH-numerous AML showed resistance to induction chemotherapy and were characterized by a very poor long-term outcome that was comparable to patients with high-risk cytogenetic or molecular genetic markers. In four patients with ALDH-numerous AML we demonstrated that the ALDHbrightCD34+CD38- subset contained chemotherapy-resistant clones with repopulating ability. Furthermore, such ALDHbright cells were characterized by a lower cell-cycle activity and an increased resistance to cytarabine in comparison with ALDHdim blasts in in vitro assays. Our data have provided evidence that LSC and residual HSC can be separated using ALDH in patients with low frequencies of ALDHbright cells. In patients with ALDH-numerous AML, the ALDHbright subset is associated with leukemic features both in vitro and in animal models. Thus our data demonstrated the feasibility of appropriate comparisons of LSC versus HSC from the same patient with specific subtypes of AML and the impact of LSC properties on clinical outcome. Disclosures: Buss: Novartis: Travel support Other; Micromet/Amgen: Reimbursements for participation in a clinical study , Reimbursements for participation in a clinical study Other. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Impact Of The Early Intensification Of Induction Chemotherapy On Complete Remission and Survival Rates For De Novo Adult Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3402-3402
Author(s):  
Seung-Ah Yahng ◽  
Jae-Ho Yoon ◽  
Sung-Eun Lee ◽  
Seung-Hwan Shin ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Remission Induction ◽  
Advisory Committees ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Background The successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. Methods A retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). Results The median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). Conclusion Our results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures: Kim: BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Impact of Day 28 Absolute Lymphocyte Count on Outcome of Adult Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5256-5256
Author(s):  
Naresh Bumma ◽  
Jing Ai ◽  
Xuefei Jia ◽  
Sean Hobson ◽  
Donna Abounader ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Lymphocyte Count ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Absolute Lymphocyte Count ◽  
Advisory Committees ◽  
The Impact ◽  
Acute Myeloid

Abstract Introduction: Lymphocyte recovery after induction chemotherapy (IC) predicts outcome in adult patients (pts) with acute myeloid leukemia (AML) (Behl et al. Leukemia 2006; 20: 29-34). However, it is unknown whether absolute lymphocyte count (ALC) recovery after IC predicts outcome in those pts who are then treated with allogeneic hematopoietic stem cell transplant (AHCT) in first complete remission (CR1). We hypothesized that the prognostic impact of ALC might be nullified by AHCT in CR1 due to the abrogation of normal immunologic recovery. In this study, our aims were to (1) evaluate the impact of Day 28 ALC on all AML pts receiving IC and (2) to specifically, evaluate the impact of Day 28 ALC on the subset of AML pts proceeding to AHCT in CR1. Methods: A retrospective chart review of 180 adult AML pts (≥ 18 years of age) who were treated with IC during the years 2001- 2012 at the Cleveland Clinic was performed. Institutional Review Board approval was obtained. Pts with acute promyelocytic leukemia were excluded . Ninety-four of the 180 pts received AHCT in CR1. A total of 141 AML pts receiving IC and a total of 66 pts receiving IC and then receiving AHCT in CR1 were eligible for data analysis because Day 28 ALC was missing in the remainder of the pts. Prior studies in AML identified an ALC of < 500/ µL at Day 28 of IC as predictive of overall survival. We stratified Day 28 ALC into the following categories: (a)< 250/ µL (b) < 350/ µL (c) < 500/ µL and (d) < 500/ µL for Max ALC [Max ALC was defined as the maximum ALC value between days 26 and 30 after the initiation of IC]. Other variables collected included age at diagnosis, WBC at diagnosis, and cytogenetic (CG) risk. CG risk was ascribed by CALBG criteria. The Kaplan-Meier method was used to summarize overall survival (OS) and relapse-free survival (RFS), which were measured for all pts from the time of diagnosis. The log-rank test was used for univariate analysis of categorical factors and the Cox proportional hazards model was used for measured factors and multivariate analysis. We performed two separate analyses : one for all AML pts (n=141); and a second analysis only focusing on those receiving AHCT in CR1 (n=66). Results: Pt characteristics for the entire AML cohort: The median age was 58.0 years (20.0-80.0); 46.1% female. The median WBC at diagnosis was 11.6 K / µL (range 0.7-220.7) and median Day 28 ALC was 400/ µL (0-2.4). Twenty-seven pts (19.7%) had favorable CG, 84 (61.3%) intermediate, and 26 (19.0%) unfavorable. Most pts (91%) received "7+3" IC and 93 (66%) also received at least 1 cycle of post-remission chemotherapy. On univariate analysis, age ≥60 (HR 2.72, p< 0.001), CG risk (HR 2.13, p < 0.001), Day 28 ALC < 250/ µL (HR 1.60, p=0.022), Day 28 ALC < 350/ µL (HR 1.57, p=0.029), and max ALC < 500/ µL (HR 1.54, p=0.035) were associated with a worse OS from the initiation of treatment. Low ALC was associated with both a higher incidence of refractory disease and death during induction (p=0.015). In our second analysis of pts undergoing AHCT in CR1, although not statistically significant, max ALC < 500/ µL (during IC) was associated with a trend towards decreased OS from the start of treatment on both univariate (HR 1.88,p= 0.13) and multivariate (HR 2.16, p=0.075) analysis. Conclusions: Max ALC < 500/ µL is predictive of outcome in AML pts undergoing IC, and there is a suggestion that this effect may not be abrogated by AHCT. A larger study will be needed to further confirm these findings. Therapies to improve lymphocyte recovery may be important in the treatment of AML. Disclosures Sekeres: Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees.

Mutational Studies Using Next Generation Sequencing in High Risk Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia Patients Treated with Azacitidine (High risk MDS 2009 protocol from CETLAM Group)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2905-2905
Author(s):  
Marta Cabezon ◽  
Joan Bargay ◽  
Blanca Xicoy ◽  
Laura Palomo ◽  
Sílvia Marcé ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Treatment Response ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Acute Myeloid

Abstract INTRODUCTION: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms originated in hematopoietic stem cells, characterized by citopenias, dysplasia in one or more cell lines, ineffective hematopoiesis and an increased risk of progression to acute myeloid leukemia (AML). Treatment of MDS depends on subtype and prognostic category. DNA methyltranferase inhibitors are approved for high risk MDS. Over the past decade, the application of new high-throughput technologies to the study of MDS has led to the identification of several recurrently mutated genes. These include genes producing proteins involved in RNA splicing, DNA methylation, chromatin modification, transcription, DNA repair control, cohesin function, RAS pathway, and DNA replication. There is a significant overlap between the genes mutated commonly in MDS with those found in AML. Mutation status is not widely used to select treatment in MDS. The aim of this study is to define the mutational status of MDS and secondary AML (sAML) patients at diagnosis that have been treated with azacitidine (AZA) to see if it could help to discriminate which patients will respond from those who will not. MATERIAL AND METHODS: A prospective study was performed on 36 patients with MDS and sAML treated with AZA. Genomic DNA was obtained from bone marrow at diagnosis. SeqCap EZ and KAPA Library Preparation Kit (Roche) reagents have been used to enrich DNA of 83 genes implicated in myeloid neoplasm. The customized panel has been analyzed in MiSeq Illumina platform with 150bp paired-end reads. Samples were preliminary analyzed using Illumina MiSeq Reporter and Variant Studio softwares. Data from response to treatment and survival have been collected from all patients. RESULTS:The mean depth of the targeted resequencing per base was 685-fold. After filtering all the variations obtained for quality, biological consequence and discard the known SNPs, we have obtained 162 variations, including 145 single nucleotide variants (SNV) and 17 insertions/deletions. All patients harbored at least 1 alteration with a mean of 4.5 variants per sample. The average of alterations detected in each cytological category can be observed in Table 1.Table 1.Average abnormalities detected by cytological category.Nº patientsAverage of alterations detected for patient (range)sAML104,8 (1-8)RAEB-274,9 (2-8)RAEB-1123,7 (1-6)RCDM54,4 (3-7)RCDM-RS16RARs11The most frequent altered genes have been TP53, TET2 and DNMT3A. The numbers of variations detected for each gene are represented in Table 2.Complete results, including correlation with treatment response will be presented in the meeting.Table 2.Number of variations in each gene.GeneNº of variations foundNº of diferent variationsNº of patients with variationsFrequency of variationsTP5322191952,8%TET214101027,8%DNMT3A88822,2%CREBBP75719,4%SRSF271719,4%ASXL165616,7%U2AF162616,7%EP30053513,9%STAG255513,9%CUX144411,1%ETV643411,1%MLL (KMT2A)43411,1%RUNX14438,3%BCOR3338,3%CDH133338,3%CTNNA13238,3%EZH23338,3%GCAT3338,3%MLL2 (KMT2D)3338,3%NF13338,3%PDGFRB3338,3%SH2B33338,3%TGM23238,3%UMODL13338,3%CEBPA2125,6%CSF3R2225,6%GATA22125,6%PHLPP12225,6%RAD212225,6%SF3B12125,6%SUZ122225,6%TIMM502125,6%Others*1112,8%*ABL1, BCORL1, CALR, CDH3, IDH2, KRAS, LUC7L2, NPM1, NRAS, PHF6, SF3A1, SFPQ, SMC3, TERT, WT1, ZRSR2. CONCLUSIONS: Targeted deep-sequencing technique is a good tool to study mutational profile in MDS and sAML. SNV are the most frequent type of alteration found in our cohort. The patients with sAML and RAEB-2 present more variations than patients with RAEB-1. The rest of groups are less representing to be evaluated. The most affected genes match with those described in the literature, with some exceptions that need to be studied in more detail. We expect to predict in advance which patients are going to respond when we study the correlation of mutational analysis with treatment response. Acknowledgments: Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (PI 11/02519); 2014 SGR225 (GRE) Generalitat de Catalunya; Fundació Josep Carreras, Obra Social "La Caixa" and Celgene Spain. Diana Domínguez for her technical assistance Disclosures Valcarcel: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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