scholarly journals Machine Learning of Genomic Factors in 1,961 Patients with Acute Myeloid Leukemia Identifies Patients with Very Good or Very Poor Prognosis Who Do Not Benefit from Allogeneic Hematopoietic Cell Transplant in First Remission

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 225-225
Author(s):  
Shaun Fleming ◽  
Cheng-Hong Tsai ◽  
Hartmut Döhner ◽  
Konstanze Döhner ◽  
Elli Papaemmanuil ◽  
...  
Keyword(s):  
Machine Learning ◽  
Research Funding ◽  
Poor Prognosis ◽  
Good Prognosis ◽  
Supervised Machine Learning ◽  
Cell Transplant ◽  
Publicly Traded ◽  
Hematopoietic Cell Transplant ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract Genomic profiling contributes to assessment of suitability for allogeneic hematopoietic cell transplant (alloHCT) in Acute Myeloid Leukaemia (AML). The ELN 2017 AML risk classification identifies patients with favorable, intermediate and adverse risk (Döhner 2017). We have used supervised machine learning (ML) to prognostically risk stratify patients with AML and explore whether prognostic groups benefit from alloHCT in first complete remission (CR1) based on pre-treatment stratification. 1961 patients were identified across the German Acute Myeloid Leukemia Study Group (AMLSG, n=1315) and National Taiwan University Hospital (NTUH, n=646) who had sufficient cytogenetic and genomic information available including the ELN 2017 cytogenetic and genomic abnormalities, spliceosome, cohesin complex and the fifteen most common genomic alterations from the Cancer Genome Atlas dataset (Ley 2013). A supervised machine learning model within R (version 4.1.0) employed a combination of random forest analysis (utilising the RandomForestSRC module version 2.11.0) and recursive partitioning (utilising the Rpart module version 4.1-15) to identify prognostic groups categorised into quintiles based upon 4-year overall survival (OS) into very poor, poor, intermediate, good and very good prognostic groups (A). Outcome according to alloHCT in CR1 was then determined by a time-dependent analysis comparing patients who in CR1 who did/or did not receive an alloHCT and were alive at 147 days (median time to transplant in the cohort). The prognostic groups were then validated against a separate AML cohort (Montreal Leucegene cohort) Patients defined by ML classification (figure 1A) to have very poor risk included patients with complex karyotype and either -7, del(7q), -17, del(17p), abn(17p) or TP53 mutations; EVI1 abnormalities (inv(3)/t(3;3)) and combined spliceosome and ASXL1 mutations. These patients had a very poor outcome irrespective of alloHCT in CR1 with a 4yr OS of 13% vs 15% (p=0.24) (alloHCT vs no-alloHCT). Patients with the combination of bi-allelic CEBPA and NRAS mutations, or the combination of NPM1, NRAS and Cohesin mutations had very good prognosis and failed to derive survival benefit from alloHCT in CR1 (4yr OS 80% vs 96% (p<0.05)) (figure 1B). Patients with either good, intermediate and poor prognosis all demonstrated improvement in OS with alloHCT in CR1 (good prognosis 90% vs 74% (p<0.05), intermediate 65% vs 50%mo (p<0.05) and poor 50% vs 31% (p<0.05)(figure 1B). ML AML classification defines two groups of patients who may not benefit from an alloHCT in CR1. Patients with very good prognosis may avoid the toxicity associated with transplantation with expectation of equivalent outcomes to those in receipt of alloHCT. Patients with very poor prognosis also fail to derive survival benefit from transplantation and represent candidates for novel post-remission strategies to improve the natural history of their disease. As this data predates the usage of FLT3 inhibitors and other novel therapies such as liposomal cytarabine/daunorubicin the impact of these therapies on patient outcome will warrant future consideration. Figure 1 Figure 1. Disclosures Fleming: Amgen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Servier: Honoraria. Döhner: AstraZeneca: Honoraria; GEMoaB: Honoraria; Novartis: Honoraria, Research Funding; Helsinn: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Agios: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Berlin-Chemie: Honoraria; Astex Pharmaceuticals: Honoraria; Astellas: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding. Döhner: Abbvie: Consultancy, Honoraria; Jazz Roche: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Agios and Astex: Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy. Tien: AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Reynolds: Abbvie: Research Funding; Alcon: Current equity holder in publicly-traded company; Novartis AG: Current equity holder in publicly-traded company. Wei: Abbvie, Amgen, AstraZeneca, Celgene/BMS, Novartis, Servier and F. Hoffmann-La Roche: Research Funding; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Honoraria; Former employee of Walter and Eliza Hall Institute: Patents & Royalties: Prof. Andrew Wei is a former employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to Venetoclax; Novartis, Abbvie, Celgene/BMS: Speakers Bureau; Abbvie, Amgen, Astellas, AstraZeneca, Celgene/BMS, Genentech, Janssen, MacroGenics, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy.

scholarly journals Acute myeloid leukemia with RAM immunophenotype: a pediatric case with unusual morphologic features

2017 ◽  
Vol 9 (2) ◽  
Author(s):  
Miriam Conces ◽  
Rolla Abu-Arja ◽  
Suzanne Reed ◽  
Hemalatha G. Rangarajan ◽  
Terri L. Guinipero ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Pediatric Case ◽  
Acute Myelogenous ◽  
Distinct Subtype ◽  
Acute Myeloid

The RAM immunophenotype has been recently described as a subtype of acute myelogenous leukemia (AML) that is characterized clinically by extremely poor prognosis. We present a case of AML with RAM immunophenotype in a 5-year-old patient that resulted in poor outcome despite early hematopoietic cell transplant. We describe the unusual morphologic features that, along with the distinct immunophenotype, may provide initial diagnostic clues and further justify the classification of this AML variant as a rather distinct subtype.

scholarly journals Hematopoietic cell transplant for acute myeloid leukemia and myelodysplastic syndrome: conditioning regimen intensity

2018 ◽  
Vol 2 (16) ◽  
pp. 2095-2103 ◽  
Author(s):  
Mary Eapen ◽  
Ruta Brazauskas ◽  
Michael Hemmer ◽  
Waleska S. Perez ◽  
Patricia Steinert ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Clinical Remission ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Key Points ◽  
Acute Myeloid

Key Points Bu4/Cy, Flu/Bu4, and Flu/Mel are optimal regimens for patients with AML in clinical remission or those with MDS. Flu/Mel, considered a less-intense regimen, is ideal for less fit patients.

Association of Iron Overload with Survival and Complications in Allogeneic Hematopoietic Cell Transplant Recipients: Prospective Cohort Study Using R2-MRI Measured Liver Iron Content

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1961-1961
Author(s):  
Bryan J Trottier ◽  
Todd E. Defor ◽  
Linda J Burns ◽  
Sarah Cooley ◽  
Navneet S. Majhail
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Liver Iron ◽  
Allogeneic Hct ◽  
Liver Iron Content ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 1961 Elevated pre-transplant ferritin levels have been associated with increased mortality and transplant-related complications in hematopoietic cell transplant (HCT) recipients. However, attempts to define the impact of iron overload on transplant outcomes using ferritin are confounded by its lack of specificity. Using liver magnetic resonance imaging (R2-MRI) to quantify liver iron content (LIC), we designed a prospective cohort study to determine the impact of iron overload on outcomes following allogeneic HCT. Our primary study objective was to determine the impact of pre-transplant iron overload on overall survival (OS); secondary objectives included cumulative incidence of non-relapse mortality (NRM) and post-HCT complications. Adult patients with hematologic malignancies being considered for allogeneic HCT were recruited for this study. Enrolled patients underwent baseline, pre-transplant ferritin measurements; patients with ferritin levels > 500 ng/ml had LIC quantified using liver R2-MRI. Patients were defined as no-iron overload (ferritin ≤ 500 or LIC ≤ 1.8 mg/gdw) and iron overload (LIC > 1.8). Of the 112 patients recruited for the study, 24 were excluded (disease progression=12, unable to complete MRI=9, transplant delays due to pre-HCT complications=3) and 88 were included in the final analysis (no-iron overload=28, iron overload=60). Four patients had ferritin >500, but on MRI had LIC ≤ 1.8 and were included in the no-iron overload group. Median ferritin in the two groups was 290 (range, 52–2023) and 1732 (range, 510–7137), respectively. The median LIC in the iron overload group was 4.3 (range, 1.9–25.4). Baseline ferritin moderately correlated with LIC (Spearman's R=0.58). There was no significant difference in recipient age, conditioning intensity, graft source, or HCT comorbidity index scores between the two groups. Patients with iron overload were more likely to have acute leukemia (55% vs 15%) and less likely to have high risk disease (40 vs 75%). We observed no significant difference in OS, NRM, relapse, acute or chronic graft-versus-host disease, organ failure, bacterial infections, viral infections, or fungal infections among patients without and with iron overload (see Table). We also found no difference in the composite endpoint of NRM, any infection, organ failure or hepatic veno-occlusive disease (1 yr cumulative incidence 71% vs 80%, P=0.44). In multivariate analyses that adjusted for other important prognostic variables, iron overload status did not impact risks of overall mortality (relative risk 2.3 (0.9–5.9) for iron overload vs. no-iron overload). We also evaluated outcomes based on an LIC threshold of ≤ 5 vs > 5 and observed similar results (see Table). Immune reconstitution studies were done in 55 patients at 3, 6 and/or 12 months post-HCT (no-iron overload=19, iron overload=36). On generalized linear mixed modeling, presence of iron overload was not associated with delay in recovery of absolute lymphocyte count, total NK cells, total T cells, CD4 cells, CD8 cells, or regulatory T cells. In conclusion, we did not find an association between pre-transplant iron-overload defined by R2-MRI measured LIC and OS, NRM, complications or immune reconstitution after allogeneic HCT in adults. Pre-transplant ferritin levels only moderately correlated with LIC. Future studies of iron overload in HCT should consider LIC to define iron overload instead of ferritin. Table. Outcomes by Iron-Overload Status Prob (95% CI) Prob (95% CI) P-value Ferritin ≤ 500 or LIC ≤ 1.8 LIC > 1.8 N 28 60 2 yr OS 78% (57–90) 58% (44–70) 0.12 2 yr NRM 18% (4–33) 21% (10–32) 0.91 1 yr Bacterial Infection 11% (0–22) 13% (5–22) 0.72 1 yr Fungal Infection 7% (0–17) 12% (4–20) 0.49 LIC ≤ 5.0 LIC > 5.0 N 65 23 2 yr OS 62% (49–73) 73% (49–87) 0.42 2 yr NRM 20% (10–30) 19% (3–35) 0.82 1 yr Bacterial Infection 12% (4–20) 13% (0–27) 0.98 1 yr Fungal Infection 12% (4–20) 4% (0–12) 0.28 Disclosures: Burns: Novartis Pharmaceuticals: Research Funding. Majhail:Novartis Pharmaceuticals: Research Funding.

Inactivating Heat Shock Factor 1 (HSF1) in Acute Myeloid Leukemia By Pharmacological Inhibition of eIF4a: A Promising Therapeutic Approach

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2548-2548
Author(s):  
Jo Ishizawa ◽  
Rodrigo Omar Jacamo ◽  
Kensuke Kojima ◽  
Dhruv Chachad ◽  
Vivian Ruvolo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Heat Shock ◽  
Cell Lines ◽  
Research Funding ◽  
Poor Prognosis ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Mrna Levels ◽  
Acute Myeloid

Abstract Heat shock factor 1 (HSF1) is best known as a key sensor of proteotoxic stress, but accumulating evidence also supports a major role for this transcriptional regulator in cancer biology. In a variety of human solid tumor cells, downregulation of HSF1 inhibits growth, induces cell death and limits metastatic potential. In breast cancers, nuclear accumulation of HSF1 and a tumor-specific gene expression signature reflecting HSF1 activation were found to be strongly associated with poor outcome (Mendillo et al, Cell 2012). In addition, we have recently reported, as a counter-intuitive reversal of the central dogma, that inhibition of protein translation represses the constitutive activation of HSF1 in cancers, and that HSF1 inhibition induced by the potent eIF4a inhibitor rohinitib (RHT) exerts profound, far-ranging anti-tumor effects (Santagata et al, Science 2013). Review of public databases supports targeting of HSF1 and eIF4a in AML: mRNA levels of HSPA8, one of the primary HSF1 targets, are correlated with poor prognosis in AML (Prognoscan, data from Metzeler et al, Blood 2008) and eIF4a mRNA levels were highest in AML among 12 cancer types (Oncomine, data from Ramaswamy et al, PNAS 2001). Here, we demonstrate that inactivation of HSF1 in acute myeloid leukemias (AMLs) by RHT exerts pronounced apoptogeniceffects with preferential activity against FLT3-ITD mutant cells in cell culture and in mice. First, we confirmed our previous finding of inactivation of HSF1 by RHT in AML. In OCI-AML3, MOLM-13 and MV4;11 cells, mRNA levels of HSPA8 were reduced by 70% after RHT treatment compared to untreated controls. OCI-AML3 cells were then infected with lentivirus encoding a reporter GFP-luciferase fusion protein the expression of which is driven by promoter elements from either the HSPA1A or HSPA6 genes; an approximately 50% reduction of reporter induction by heat shock was observed after RHT treatment compared to untreated controls. Next, treatment of 7 human AML cell lines in culture showed that RHT induces marked anti-leukemia effects at low nanomolar concentrations (LD50s; 9.5 to 99.5 nM, IC50s; 4.7 to 8.8 nM, based on AnnexinV/PI-positivity as determined by flow cytometry at 72hr). The most pronounced cytotoxic effects were observed in FLT3-ITD+ cell lines (LD50s < 10 nM in MOLM13 and MV4;11 cells). Using two sets of isogenic cell lines (Ba/F3 and OCI-AML3 cells with FLT3-ITD or wild-type (wt) FLT3), we confirmed that RHT more potently kills FLT3-ITD cells (LD50s; 65.3 vs 20.1 nM in Ba/F3 cells). Furthermore, the combination of FLT3 inhibitor sorafenibwith RHT showed synergistic effects in cell culture (Combination Index: ED50 0.85, ED75 0.86, ED90 0.89). Immunoblot analysis showed higher phospho-HSF1 (Serine 326) in FLT3-ITD Ba/F3 cells than FLT3-wt cells, suggesting greater dependence of FLT3-ITD cells on HSF1 activation for survival. We also tested primary samples from 17 AML patients and bone marrow (BM) samples from 8 healthy donors. RHT potently induced apoptosis in AML cells, while relatively sparing normal BM cells (Figure 1A). Importantly, a similarly significant difference in sensitivity was also observed between AML and normal stem cells (CD45+CD34+CD38-). Moreover, the activity of RHT against the leukemic population was significantly higher in FLT3-ITD than in FLT3-wt cells (Figure 1B). We also evaluated the activity of RHT in a FLT3 mutant AML xenograft model using GFP-luciferase labeled MOLM-13 cells. Significantly decreased luciferase activity was detected by bioluminescence imaging and a dose-dependent reduction in GFP+ leukemic cells was seen in peripheral blood and BM by day 16 (Figure 2). Survival of the treatment groups was significantly prolonged (median; 18 vs 22.5 vs 24 days respectively, p < 0.0001). In conclusion, HSF1 function provides an attractive therapeutic target in AML. The eIF4a inhibitor RHT down-regulates HSF1 transcriptional function and exerts robust anti-leukemia activity in cell culture and in mice. Although the relative contributions of HSF1 inactivation and translation inhibition to the net anti-leukemic activity of RHT remain to be defined, promising features of this approach include its activity against AML stem cells, while sparing normal stem cells and its particularly potent cytotoxicity for poor-prognosis FLT3-ITD AMLs. Taken together, these preclinical findings strongly support further development of eIF4a inhibitors in the treatment of AML. Disclosures Ishizawa: Karyopharm: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

In the Era of Bortezomib-Based Chemotherapy the Presence of Minimal Residual Disease Predicts Progression Free Survival after Autologous Hematopoietic Cell Transplant

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5493-5493
Author(s):  
Robert F Cornell ◽  
Jade E Jones ◽  
Claudio A. Mosse ◽  
Heidi Chen ◽  
Laura Dugger ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Research Funding ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Free Survival ◽  
Kaplan Meier ◽  
Minimal Residual

Abstract Background: Retrospective studies have shown that achieving minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) is predictive of outcomes in multiple myeloma (MM). Modern induction therapies including bortezomib (V), lenalidomide (R) followed by autologous hematopoietic cell transplant (AHCT) have resulted in substantial improvements in progression free survival (PFS) and overall survival (OS). The impact of bortezomib-based therapy on end of induction chemotherapy MRD status and post-AHCT MRD status is not well defined. We designed a prospective clinical trial (NCT01215344) to study the incidence of MRD negativity at end of induction and following AHCT, and its association with PFS and OS. Patients and Methods: Twenty patients with newly diagnosed, symptomatic MM were enrolled. They received four cycles of VRd induction therapy followed by AHCT. Dose modifications of VRd were controlled during the clinical trial. MRD status by MFC was evaluated at the end of induction chemotherapy and at day 100 post-AHCT. The MFC cut-off to determine MRD negativity was defined as 10-4. Outcomes analyzed included MM disease status, PFS and OS. Results: Three cohorts of patients were identified; patients achieving MRD negative status at the end of induction (cohort 1, 50%), those achieving MRD negative status only after AHCT (cohort 2, 15%) and patients never achieving MRD negative status (cohort 3, 35%). All patients achieving MRD negative status at the end of induction remained MRD negative post-AHCT. There were no significant differences in median age, renal function, disease stage, cytogenetic risk and maintenance chemotherapy post-AHCT between cohorts. The table summarizes characteristics of these cohorts. Patients who never achieved MRD negative status after AHCT had significantly shorter PFS (cohort 3) compared with patients who achieved MRD negative status (cohorts 1 and 2, p=0.008) (figure). The median PFS for cohort 3 was 2.64 years and not yet reached for the other cohorts. There were no significant differences in OS. Median follow-up for survivors was 2.53 years (range, 0.73-4.04). Conclusions: In this study, bortezomib-based therapy resulted in half of patients achieving MRD negative status with induction chemotherapy alone. AHCT improved the depth of response with 30% of patients who were MRD positive after induction therapy converting to MRD negativity following AHCT. Achieving a negative MRD state, pre- and at D100 post-AHCT resulted in improved PFS. These findings were independent of molecular cytogenetics or ISS stage. MRD positive status at day 100 post-AHCT is highly predictive of earlier disease progression, and may help identify patients for alternative management approaches. Delay of AHCT may be considered as a potential management option for patients with MRD negative status at the end of induction therapy, as being studied in the IFM DFCI study (NCT01208662). As some patients with MRD positive disease at the end of induction therapy become MRD negative with AHCT, these patients may benefit from AHCT and this population warrants further investigation. Table. Descriptive analysis Cohort 1 MRD -/- (%) (n=10) Cohort 2 MRD +/- (%) (n=3) Cohort 3 MRD +/+ (%) (n=7) Test Statistic Median Age 55 54 60 0.31 ISS Stage III 40 33 14 0.52 DS Stage III 89 67 60 0.14 Median Serum creatinine 0.90 0.60 0.88 0.10 Serum M-spike 2.0 1.9 2.1 0.80 Bone marrow plasma cells 14 44 14 0.18 Cytogenetics 0.37 Standard risk 40 0 57 Intermediate risk 50 67 43 High risk 10 33 0 Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Figure 1. Kaplan-Meier curve of progression-free survival comparing patients achieving MRD negative disease with MRD positive disease. Disclosures Cornell: Prothena: Research Funding. Jagasia:Takeda Inc: Research Funding.

scholarly journals Age-Based Probability of Ten-Year Overall Survival (OS) of Acute Myeloid Leukemia (AML): A National Cancer Database (NCDB) Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Vijaya R. Bhatt ◽  
Valerie K Shostrom ◽  
Nabin Khanal ◽  
Chakra P Chaulagain ◽  
Fiona He ◽  
...  
Keyword(s):  
Older Patients ◽  
Research Funding ◽  
Clinical Trial Data ◽  
Older Age ◽  
New Drugs ◽  
Cell Transplant ◽  
Short Term ◽  
Hematopoietic Cell Transplant ◽  
Logistic Regression Models

Background: Clinical trial data suggest excellent short-term outcomes for younger patients and a subset of fit older patients. Translating findings of clinical trials into the real-world practice has challenges, and longer-term data are often not available. Hence, we utilized NCDB to determine age-based probability of ten-year OS of unselected cohorts of adults with AML. Methods: NCDB captures about 70% of all new diagnosis of cancer. We utilized NCDB to analyze ten-year OS of 15,646 patients aged ≥18 years, who were diagnosed with AML during the years 2004-2007. Univariate and multiple logistic regression models were used to determine factors associated with ten-year OS. Kaplan Meier curves were generated for OS analysis. Results: Ten-year OS was 12.7% for patients aged 18-59 years treated with chemotherapy without hematopoietic cell transplant (HCT) (Table 1, Fig. 1). Older age, male, Charlson-Deyo comorbidity score &gt;0, insurance other than private, subtypes other than core-binding factor AML were associated with lower ten-year OS. Ten-year OS was 24.3% for patients aged 18-59 years treated with chemotherapy and HCT (Fig 2). Older age, male, and insurance other than private were associated with lower ten-year OS. Ten-year OS was 16.1% and 2.2% for patients older than 60 years and treated with and without HCT, respectively; multivariate analysis was not performed for older patients because of low sample size (HCT group) or low survival (non-HCT group). Detailed analysis will be presented. Conclusions: Long-term OS of adults with AML is low with less than a quarter of patients being alive at ten years. Ten-year OS is particularly poor for older patients who are treated with chemotherapy alone. Whereas recent advances and approval of eight new drugs will likely improve short-term OS at 2-3 years, innovative strategies are necessary to improve long-term OS and cure. Further study to identify the cause of death will be insightful. Disclosures Bhatt: Takeda: Consultancy; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Research Funding; Tolero: Research Funding; Rigel: Consultancy; Agios: Consultancy; Omeros: Consultancy. Chaulagain:Sanofi Genzyme: Honoraria. Gundabolu:BioMarin: Consultancy; Bristol Myers Squibb pharmaceuticals: Consultancy.

scholarly journals Evaluating the Efficacy of PRMT5 Inhibitor C220 in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1170-1170
Author(s):  
Anilkumar Gopalakrishnapillai ◽  
Anne Kisielewski ◽  
Yang Zhang ◽  
Bruce Ruggeri ◽  
Peggy Scherle ◽  
...  
Keyword(s):  
Median Survival ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Publicly Traded ◽  
Pediatric Acute Myeloid Leukemia ◽  
Patient Derived Xenograft ◽  
Pediatric Aml ◽  
Pdx Models ◽  
Acute Myeloid

Abstract Pediatric acute myeloid leukemia (AML) is the deadliest malignancy in children. Despite maximally intensive therapy, inclusive of chemotherapy and hematopoietic stem cell transplant, approximately 20% of patients experience recurrent disease. These patients are also burdened with treatment-related toxicities. Significant improvements in survival in pediatric AML patients necessitate the incorporation of rational targeted therapies with reduced toxicity. Recent studies demonstrate that PRMT5 knockout or inhibition in syngeneic mouse models of KMT2A (MLL) rearranged leukemic cells increased disease latency (Serio et al., Oncogene, 37:450, 2018; Kaushik et al., Leukemia, 32:499, 2018), indicating that PRMT5 is a potential therapeutic target in pediatric AML. However, there are no reports testing the efficacy of PRMT5 in PDX models of pediatric AML. We evaluated the preclinical efficacy of C220, a potent and selective PRMT5 inhibitor (PRMT5i) (Pastore et al., Cancer Discovery, 10:1742, 2020) in three distinct patient-derived xenograft (PDX) models of KMT2A rearranged AML. Based on the model used for the study, 3-5 million AML cells were injected intravenously in NSG-B2m mice. Disease progression was monitored by evaluating the percentage of human cells in mouse peripheral blood at periodic intervals by flow cytometry. At 2-3 weeks post transplantation, when human cells were detectable in peripheral blood, mice were randomly assigned to control (n=4-5) or treatment (n=2) groups. C220 was administered daily p.o. at a dose of 15 mg/kg for seven days with a break of two days. Mice were dosed with 2-3 additional cycles (indicated in the figure by shaded areas) based on their health status. Mice were monitored daily for experimental endpoints that included body condition score and human cell percentages in peripheral blood. Kaplan-Meier survival plots were generated based on the time when mice were euthanized because they met experimental endpoints. Chronic dosing of C220 prolonged survival and delayed the rise in percentage of human AML cells in mouse peripheral blood in all 3 PDX models (Fig. 1B, D, F). In the NTPL-146 model (KMT2A-MLLT1 fusion), a 135-day improvement in median survival was observed with C220-treatment (Fig. 1A). In the DF-2 (KMT2A-MLLT10 fusion) and DF-5 (KMT2A-MLLT4 fusion) models, which showed a faster engraftment compared to NTPL-146, there was a 5.5-day and 18-day improvement in median survival respectively (Fig. 1C, E). The improvement in median survival was statistically significant in all models (*P&lt;0.05). In conclusion, C220 was effective in controlling leukemia progression and improving survival in KMT2A rearranged PDX models of pediatric AML. Figure 1 Figure 1. Disclosures Gopalakrishnapillai: Geron: Research Funding. Zhang: Prelude Therapeutics: Current Employment. Ruggeri: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Scherle: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Barwe: Prelude Therapeutics: Research Funding.

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