Cytogenetic Risk Group Research Articles

Prognostic Impacts of Additional Cytogenetic Abnormalities Acquired at the First Relapse in Adult Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplant in Second Complete Remission

Background: Additional cytogenetic abnormalities (ACA), the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of leukemia cells. Recently, we described that ACA at the first relapse was associated with the significantly lower second complete remission (CR2) rate and poor survival in adult acute myeloid leukemia (AML) patients (Hematol Oncol. 2018;36:252-257). However, the prognostic impact of ACA after allogeneic stem cell transplant (allo-SCT) has not been elucidated in adult AML patients. Patients and methods: Of the 145 adult AML patients who underwent the first allo-SCT in CR2 between 1997 and 2019, 98 patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. Cytogenetic changes between at diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the first relapse. In this study, groups 2 and 4 were defined as ACA acquisition. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Cox and Fine-Gray proportional hazard model were used for multivariate analysis of prognostic and risk factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 98 patients included in this study, 57 were male, and 41 were female. The median age at transplant was 45 years (range, 17-71 years). The median duration of CR1 was 12.4 months (range, 1.3-70.3 months) and cytogenetic risk groups were good, intermediate, and poor in 26 (27%), 70 (71%), and two patients (2%), respectively. Donor types were related, unrelated, and cord blood in 23 (24%), 59 (60%), and 16 patients (16%), respectively, and 86 (87%) and 61 patients (62%) were conditioned with myeloablative and total body irradiation-containing regimens, respectively. According to the definition described above, 20 patients (20%) acquired ACA at the first relapse. There was no significant difference in baseline characteristics and transplant procedures between patients with and without ACA acquisition. The OS rates were not significantly different between two groups (55% vs. 72% at three years after transplant; p = 0.28). The CI of relapse was significantly higher in patients with ACA acquisition than those without ACA acquisition (59% vs. 15%; p < 0.01), while the CI of NRM were not significantly different between two groups (5% vs. 19%; p = 0.17). Multivariate analysis for OS revealed that age over 50 years (hazard ratio [HR] = 2.4; p < 0.01), but not ACA acquisition, was identified as an independent prognostic factor. ACA acquisition (HR = 4.7; p < 0.01) was extracted as an independent risk factor of relapse, while use of reduced intensity conditioning regimens (HR = 3.1; p = 0.03) and more than or equal to 1 of performance status at transplant (HR = 2.7; p = 0.04) showed independent risks of NRM. The similar OS rates between two groups might resulted from an offset of the lower relapse rate with the higher NRM rate in patients without ACA acquisition despite not reaching statistical significance. This increasing NRM rates in those without ACA acquisition was potentially associated with use of reduced intensity conditioning regimens in larger proportion (0% vs. 15%; p = 0.12). Conclusion: These findings suggested that ACA acquisition at the first relapse was associated with a higher risk of relapse even after allo-SCT in CR2 in adult AML patients. As AML cells with ACA acquisition was resistant to not only chemotherapy but also graft-versus-leukemia effect, innovative therapeutic strategy is warranted. DisclosuresHanda: Janssen: Honoraria; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Chugai: Research Funding; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding.

Response Kinetics of Daratumumab-Based Regimens in Patients with Newly Diagnosed or Refractory/Relapsed Multiple Myeloma

Background: It is controversial in multiple myeloma (MM) whether early and late responders to therapies have similar clinical outcomes. Daratumumab (DARA) is a human anti-CD38 antibody that has been increasingly used in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The association between response kinetics to DARA and clinical outcomes remains unexplored.Methods: Individual-participant data were obtained from phase 3 trials: POLLUX (Dimopoulos, NEJM, 2016), CASTOR (Palumbo, NEJM, 2016), and MAIA (Facon, NEJM, 2019). Patients were divided into early and late response groups based on the median time to the response of interest. Modified PFS (mPFS) and OS (mOS) were calculated from the time of first response of interest. Minimal residual disease (MRD) negativity was defined as less than 10 5 tumor cells by NGS assays.Results: After a median follow up of 16.1 months, 670 patients achieved a response of very good partial response (VGPR) or better, and 213 achieved MRD negativity. The median time to achieving VGPR or better was similar between NDMM and RRMM (86 vs. 84 days, respectively), while the median time to MRD negativity was longer among NDMM than RRMM (407 vs. 197 days, respectively). Among patients achieving VGPR or better, there was no significant difference of mPFS (HR 1.00, 95%CI 0.69 to 1.44) (fig. a), duration of response (DOR) (HR 1.02, 95%CI 0.68 to 1.53) (fig. b), or mOS (HR 0.98, 95%CI 0.54 to 1.75) (fig. c) between early and late responders. In the subgroup analysis, no significant difference of DOR was observed across all prespecified groups, including sex, age, cytogenetic risk groups, lines of previous therapy, types of measurable disease, NDMM vs. RRMM, prior treatment with autologous hematopoietic cell transplant, immunomodulatory drugs, or proteasome inhibitors. Among patients with NDMM achieving MRD negativity, there was no significant difference of mPFS (p=0.66) (fig. d), DOR (p=0.21) (fig. e) or mOS (p=0.87) (fig. f) between early and late responders. However, among patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS (p=0.038) (fig. g) and DOR (p=0.043) (fig. h) than early responders; mOS was not significantly different (fig. i). In the multivariable Cox analysis among patients achieving MRD negativity, only lower baseline LDH level, NDMM, and IgG type MM were independently associated with later response.Conclusions: For patients with NDMM or RRMM achieving VGPR or better, early and late responders had similar survival; for patients with RRMM achieving MRD negativity, late responders had significantly longer mPFS and DOR. Our data support that in patients who failed to achieve an early or deep response to daratumumab based regimens, therapies should be continued with the goal of achieving ongoing and stepwise improvement of response. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical, Cytogenetic Characteristics and Survival of Acute Leukemia in a National Research Center Database, 10-Year Real-World Data Review

IntroductionMajor resources of our current knowledge on acute leukemia epidemiology and prognosis are based on data from clinical trials. Due to the selective bias of clinical trials, data might differ from the general leukemia population in real-life setting. National Clinical Research Center for Blood Disease established a comprehensive database through the electronic health records (EHR) to facilitate research of the hematologic cancers i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and acute promyelocytic leukemia (APL). The aim of the database is to gain insight into the epidemiology of these cancers, to evaluate treatment responses, to compare results between geographical regions of China. Furthermore, with the privilege of national research center, the database expects to identify prognostic and predictive factors for outcome to improve the quality of treatment and patients care.MethodsThe database development was initiated in 2001. Standard data elements were established to capture the key clinical variables. For individual patients, data from EHRs were extracted, integrated and quality checked. The implement of database facilitated the clinical professions to identify eligible patients, establish research projects, conduct retrospective analysis and follow-up patient outcomes. Continued efforts were made for improving the construction and quality of the database over two decades.We performed a 10-year real-world data review in the database to evaluate the quality of the recorded data and, moreover to describe the clinical, cytogenetic characteristics and survival of acute leukemia patients. The completeness for collected variables was acceptable for statistical analysis. In total, 3,404 patients (1,895 males and 1,509 females) who were diagnosed and treated between Jan. 1, 2010 and Dec. 31, 2020 were enrolled. A substantial proportion (>60%) of patients were residents of the northern and northeast region of China. Demographic and baseline characteristics also included age, age class, baseline blood test, transplantation and research participation. Molecular mutations such as nucleophosmin-1 (NPM1), FMS-related tyrosine kinase 3 (FLT3), and CCAAT/enhancer-binding protein alpha (CEBPA) et al were included in the screening panels. We explored the treatment remission rate and prognosis of different chromosomal karyotype groups among AML patients.ResultsThe patient numbers of the AML, ALL and APL subgroups were 2,345, 769 and 290 respectively. Blood routine results well demonstrated the clinical characteristics of each subgroup (Tbl. 1). In AML group, the frequencies of NPM1, FLT3-ITD, KIT and CEBPA double mutations were 17.9%, 13.2%, 8.7% and 10.1%, respectively (Tbl. 2). In term of ALL, 640 cases (83.2%) were B-ALL and 129 (16.8%) were T-ALL. Among B-ALL, 256 cases (33.3%) were Ph positive. 10-year analysis for overall survival shown that AML patients had better outcomes as compared with ALL group (Fig. 1). In this database, 1,780 AML cases (excluding APL) were enrolled in cytogenetic analysis. The survival rates of different cytogenetic risk groups from our real-world data were separated by the ELN2017 and MRC risk stratification respectively (Fig. 2A-B). Remarkably, we found two rare but recurrent abnormalities, 16 cases with t(7;11) (p15;p15) and 12 cases with t(16;21)(p11;q22/q24;q22). Cases showed high relapse and mortality rate. Compared with the normal karyotype group, the survival of both subentities was worse and transplantation might be recommended in CR1 phase (Fig. 2C), therefore, we recommend that these two subtypes might be regarded as the worse risk group, although neither is mentioned in the current guidelines. The incidence of t(8;21) in our database was 17.9% (Fig. 3). To explore the impact of additional chromosomal abnormalities on the prognosis of t(8;21), we found that the overall survival of patients with additional trisomy 4 was worse than those without trisomy 4 (Fig. 2D), which was rarely mentioned in previous reports.ConclusionThe real-world database is of great importance for defining the comprehensive features of AML, APL and ALL in clinical setting. The results offered a remarkable contribution to our knowledge on acute leukemia and identified the prognosis of rare chromosomal karyotype in AML. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

High-Throughput Characterization of Cytogenomic Heterogeneity of MDS Using High-Resolution Optical Genome Mapping

IntroductionIntroduction of next-generation sequencing has defined the somatic mutational landscape in MDS. Comprehensive high-throughput structural variant profiling (SVP) is as important as mutation profiling in characterizing MDS clonal architecture since these large genomic aberrations have already shown to be critical for diagnosis and risk-stratification of MDS. A subset (MECOM, KMT2A rearrangements) are therapeutic targets in clinical trials. At this time, technical advances in SVP for copy number alterations (CNAs) and fusions have not been congruent with mutation profiling due to the inability of short-read (150bp) NGS to detect SVs. Currently available long-read (10-20Kbp) and whole genome sequencing cannot detect all SVs due to the presence of repeat sequences. Hence, conventional karyotyping (CK) remains the gold standard. Optical genome mapping (OGM) is a novel single-platform technique that measures ultra-long-range sequence patterns (>300Kbp), thereby unaffected by repeat sequences, enabling unbiased evaluation of all types of SVs at a high resolution. Here, we performed comprehensive SVP and mutation profiling in a large well-characterized cohort of MDS.MethodsWe selected samples with available fresh/frozen BM cells from consecutive treatment-naïve MDS pts who also underwent standard-of-care tests (CK, FISH, targeted 81-gene NGS for mutations). For OGM, ultra-high-molecular-weight-DNA was extracted, followed by labeling, linearization and imaging of DNA (Saphyr, Bionano) [median coverage:>300X]. The results were analyzed using de novo (>500 bp), rare variant (>5000 bp) and copy number (>500,000 bp) pipelines. The data was compared against 200 healthy controls to exclude common germline SVs. Clinical significance of the SVs was determined based on the location/overlap with the coding region of myeloid malignancy associated genes. The detection sensitivity was 10%.ResultsThere were 76 treatment naïve MDS patients. Baseline characteristics, comprehensive cytogenetic scoring system (CCSS) and R-IPPS risk categories and somatic mutations are in Fig 1.OGM identified all clonal abnormalities detected by CK [CNAs, inversions, inter/intra-chromosomal translocations, dicentric, complex derivative chromosomes]. Precise mapping of SVs by OGM at gene-level allowed determining the status of clinically informative biomarkers such as TET2, MECOM, TP53 and KMT2A, without the need for confirmatory assays. Detailed gene-level characterization of different SVs included KMT2A-ELL [t(11;19)] in MDS with WT1 mut, t(9;11) with SYTL2 fusion (and not KMT2A), der(1;7) leading to del(7q) in MDS with GATA2 mut/IDH2 mutand t(1;3)(p36;q21) rearrangements with potential PRDM16 disruption in SF3B1 mut/RUNX1 mutMDS, among others. Using OGM, we mapped the sequence patterns in both samples with IM with high level of confidence.Additionally, OGM identified 23 cryptic, clinically significant SVs in 14 (18%) of 76 pts. These included deletions of TET2, KMT2A, and del(5q), KMT2A amplification in MDS with FLT3-ITD/DNMT3A mut/RAS mut, NUP98-PRRX2, MECOM rearrangement in TET mut mutated NK-MDS. In addition, there were SVs of uncertain significance: duplications of chr1 (PDE41P), deletions of chr21 (involving RUNX1), chr2 (DNMT3A, ASXL2), chr12 (ETV6) and chr22 (EP300) and der(16)t(12;16)(q21.1;q12.1). These cryptic SVs were noted across all R-IPSS risk categories (highest yield in very-low and low R-IPSS) and across all cytogenetic risk-groups (very-good to very-poor).In complex karyotype setting, OGM could resolve the markers and additional genetic material, and in most cases, showed a much higher the degree of complexity within the genome than was apparent by CK. Four pts showed SV patterns typical of chromothripsis/chromoplexy.The median number of mutations per pt was 1 (0-6). When compared to mutation subsets, cryptic SVs were only identified in pts with ≤3 mutations. Majority represented either MDS with TP53 mut (6, 29%) or SF3B1 mut/TET mut (deletions of TET2, KMT2A, NOTCH1 and EP300 genes).ConclusionsUnbiased, high-throughput whole genome SVP revealed cryptic, clinically significant SVs in ~18% of MDS pts. OGM is a single-platform cytogenomic tool that can facilitate SVP at a gene-level resolution. This study provides strong support for further validation in expanded cohorts to guide clinical implementation and integration of SVP for routine work-up. [Display omitted] DisclosuresWei: Daiichi Sanko: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

Non-Age-Related Neoplastic Loss of Sex Chromosomecorrelated to Prolonged Survival in CBF-AML Patients in Real-World Clinical Setting

IntroductionSince Core-binding factor acute myeloid leukemia (CBF-AML) is categorized as a favorable cytogenetic risk group, allogenic hematopoietic stem cell transplantation (HSCT) is generally not recommended during the first complete remission (CR1). However, approximately 30-50% of CBF-AML patients relapse, and about 50% of relapsed patients remain incurable. Therefore, in real-world clinical setting, the indication of HSCT even in CR1 is considered based on prognosis prediction and minimal residual disease (MRD) status. With respect to prognosis prediction by chromosomal abnormalities, the prognostic impact of loss of sex chromosome (LOS) in the patients with CBF-AML is still controversial. Previous studies suggest that the impact of LOS in predicting the prognosis of CBF-AML may depend on treatment strategies including HSCT. In addition, although CBF-AML develops LOS at a high rate of 20-40%, it is still unclear whether LOS is age-related or neoplastic.MethodsHokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG).Cases of CBF-AML that were registered in HLN from January 2010 to December 2019 were used for analysis in the present study. All the patients received either intensive or low-intensity chemotherapy. HSCT was performed at the discretion of the attending physicians even in CR1. Conventional cytogenetic analysis was performed at the time of diagnosis and after each treatment. FLT3-ITD and KIT exon17 mutations were analyzed using genome DNA template at the central laboratory. The results of genetic analysis were returned to physicians so that they could reflect the genetic result in their treatment choice. We evaluated the impacts of several factors including advanced age, poor response to chemotherapy, LOS, and KIT exon17 mutation on overall survival (OS) and relapse-free survival (RFS) in these patients. This study was conducted in compliance with ethical principles based on the Declaration of Helsinki and was approved by the institutional review board of Hokkaido University Hospital.ResultsA total 96 CBF-AML patients including 62 patients with RUNX1/RUNX1T1 and 34 patients with CBFβ/MYH11 were enrolled in the present study. Intensive induction chemotherapy using '7+3' cytarabine plus anthracycline and low-intensity induction chemotherapy were performed in 90 patients and 6 patients, respectively. In 90 patients who underwent intensive induction chemotherapy, the CR rate after one cycle of induction therapy was 73.3%. Total CR rate as the best response was 91.7% for all CBF-AML patients. HSCT in CR1 was performed in 15 patients (15.6%) at the discretion of the attending physician based on genetic alterations, poor response to chemotherapy, and sustained detection of MRD after chemotherapy. There was no significant difference in 5-year OS (RUNX1/RUNX1T1 64.9% vs CBFβ/MYH11 52.9%; P=0.546) or 5-year RFS (63.6% vs 53.3%; P=0.364) between the CBF subtypes. LOS was significantly more frequent in patients with RUNX1/RUNX1T1 than in patients with CBFβ/MYH11 (35.5% vs 5.9%; P=0.001). Multivariate analyses for 5-year OS in CBF-AML patients revealed that age of 50 years or older (HR: 3.46, 95% CI: 1.47-8.11, P=0.004) and receiving 2 or more induction cycles (HR: 3.55, 95% CI: 1.57-8.05, P=0.002) were independently associated with worse OS and that LOS was independently associated with better OS (HR: 0.09, 95% CI: 0.01-0.71, P=0.022). We next sought to clarify whether LOS was age-related or neoplastic based on the transition of chromosome results. All the 24 patients with LOS achieved CR, and chromosome analysis at CR showed a normal karyotype in all of the 21 patients for whom chromosome analysis was performed. In the remaining 3 patients, only FISH analysis for RUNX1/RUNX1T1 or CBFβ/MYH11 was performed. Furthermore, chromosome analysis showed mosaics of metaphase cells with and without t(8;21) in 9 patients at diagnosis. In all of those patients, metaphase cells without t(8;21) showed a normal karyotype.ConclusionIn our real-world clinical setting in which '7+3' induction was performed and the indication of HSCT was determined by prognostic factors and MRD status, LOS correlated to prolonged survival in CBF-AML patients. Furthermore, the transition of chromosome results revealed that LOS was not age-related physiological loss but part of neoplastic chromosomal abnormalities. [Display omitted] DisclosuresTeshima: CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Janssen Pharmaceutical K.K.: Other; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol Myers Squibb: Honoraria; Fuji pharma CO.,Ltd: Research Funding; Pfizer Inc.: Honoraria; Sanofi S.A.: Research Funding. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy.

Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics.Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD.Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p<0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2).Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. [Display omitted] DisclosuresBeksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.

Immunogenetic, Molecular and Clinical Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Immunogenetic, Molecular and Clinical Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Upfront Autologous Stem Cell Transplantation (ASCT) Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Consolidation in Transplant-Eligible, Newly Diagnosed (NDTE) Multiple Myeloma (MM): Results of the Cardamon Study According to Cytogenetic Risk

Upfront Autologous Stem Cell Transplantation (ASCT) Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Consolidation in Transplant-Eligible, Newly Diagnosed (NDTE) Multiple Myeloma (MM): Results of the Cardamon Study According to Cytogenetic Risk

Secondary Acute Myeloid Leukemia (sAML): Similarly Dismal Outcomes of AML After an Antecedent Hematologic Disorder and Therapy Related AML

Therapy related acute myeloid leukemia (tAML) and secondary AML after an antecedent hematologic disorder (sAML-AHD) are often addressed together, blurring any clinical and prognostic differences. Among 516 AML patients, we compared characteristics and outcomes of 149 patients with “sAML” (sAML-AHD: 104, tAML: 45), uniformly and intensively treated during the last 2 decades at 1 center. Clinical outcomes of the whole “sAML” cohort were significantly inferior compared to de novo AML and in both intermediate and poor cytogenetic risk groups. Adverse karyotype had no effect on survival in tAML, while it was a negative predictor in sAML-AHD. Both groups showed similarly dismal outcome, with low complete remission rates (CR 44% vs. 41%) and median overall survival (OS 7 vs. 10.5 months). Allogeneic hematopoietic cell transplantation (alloHCT) recipients in CR1 had superior median OS (24 vs. 8 months). By multivariate analysis, alloHCT was an independent predictor of outcome, while karyotype was for sAML-AHD only. In conclusion, both “sAML” groups have inferior outcomes after chemotherapy, with adverse karyotype affecting primarily sAML-AHD. Until new treatment approaches are available, only alloHCT offers a survival advantage.

P-001: Modulation of soluble B-cell maturation antigen levels in patients with relapsed and/or refractory multiple myeloma after treatment with teclistamab and talquetamab

<h3>Background</h3> B-cell maturation antigen (BCMA, CD269), a single transmembrane protein, can be shed as a soluble 6 kilodalton protein fragment (sBCMA) upon cleavage at the transmembrane domain by γ-secretase. Given its selective expression in the B-cell lineage, BCMA is a validated target for multiple myeloma. Teclistamab and talquetamab are CD3 bispecific antibodies developed to recruit CD3+ T cells to BCMA+ or G protein-coupled receptor family C group 5 member D (GPRC5D)+ multiple myeloma (MM) cells, respectively. Levels of sBCMA after teclistamab or talquetamab treatment were evaluated in patients with relapsed and/or refractory MM (RRMM). <h3>Methods</h3> Serum samples from patients with RRMM in teclistamab and talquetamab phase 1 studies (64007957MMY1001 and 64407564MMY1001, respectively) were collected at various timepoints between baseline and cycle 4 or end of treatment and analyzed for sBCMA by an electrochemiluminescence ligand binding assay. Quantitative analyses of sBCMA data were conducted with reference to a patient's tumor burden and response, and to pharmacokinetic data. <h3>Results</h3> Teclistamab and talquetamab modulated levels of sBCMA in patients with high (≥50%) and low (<50%) frequency of tumor plasma cells (TPCs) and in high and low risk cytogenetic groups. In cycle 3, a majority of the responders showed sBCMA reductions (teclistamab: 88% [50/57]; talquetamab: 98% [49/50]) compared with baseline. In contrast, non-responders (progressive disease/ stable disease/ minimal response) showed an increase in sBCMA (teclistamab: 80% [33/41]; talquetamab: 49% [24/49]) compared with baseline. A higher magnitude of sBCMA reductions was noted in patients with deep responses. In a few patients who initially responded to teclistamab or talquetamab and then relapsed, sBCMA levels trended toward an initial reduction followed by an increase. Levels of sBCMA correlated with % bone marrow TPCs. A majority of patients with plasmacytoma (based on limited data) appeared to have high sBCMA levels, suggesting that sBCMA could be a comprehensive marker for tumor burden. Teclistamab preliminary population pharmacokinetic analysis showed that sBCMA did not appear to impact teclistamab exposure, suggesting that sBCMA does not act as a sink for teclistamab. <h3>Conclusions</h3> Changes in the levels of sBCMA upon treatment with teclistamab and talquetamab correlated with clinical activity, supporting further clinical development. The findings support BCMA as a potential surrogate marker of myeloma tumor burden and as a valuable marker for response in patients with MM.

AML-176: Characteristics, Treatment Patterns and Predictors of Outcomes in Treatment-Naive Acute Myeloid Leukemia Patients Judged Ineligible for Intensive Chemotherapy in Sweden

Context: There is limited recent population-based data on outcomes for novel agents and different treatment combinations in acute myeloid leukemia (AML) patients judged ineligible for intensive chemotherapy. Objective: To characterize patients, treatment patterns, and predictors of overall survival (OS) in treatment-naive AML patients judged ineligible for intensive chemotherapy. Design: A retrospective population-based study using data from the National Board of Health and Welfare, the Swedish AML Register, and medical records. Patients: Incident AML patients from 2012 to 2019 that were judged ineligible for intensive chemotherapy (n=1,335). Among a subgroup of patients with detailed information on treatment patterns and responses, patients with a hypomethylating agent (HMA; n=120) or low-dose cytarabine (LDAC; n=18) were selected for subgroup analyses. Patients were followed until death or censoring in 2020. Main Outcome Measures: Time-varying hazard ratios (HRs) for OS with 95% confidence interval (CI) for the calendar period for AML diagnosis, first-line treatment type, sex, age, AML etiology, and cytogenetic risk group. Responses were defined as complete remission (CR), including CR with incomplete hematological recovery, or primary induction failure. Results: In total, 122 (19.3%) and 278 (39.6%) patients received HMA during the earlier and later calendar periods (2012–15 and 2016–19), respectively. Among all patients, the median OS from AML diagnosis was 2.52 (95% CI 2.28–2.88) months. First-line treatment exposure to novel agents (HMA or venetoclax) compared to palliative or other low-intensive treatment was associated with lower risk of death at 1 years after AML diagnosis (HR 0.26 [95% CI 0.21–0.31], 0.39 [95% CI 0.29–0.53], and 0.62 [95% CI 0.40–0.95], respectively). Age at AML diagnosis, sex, AML etiology, and calendar period of diagnosis were not significantly associated with OS in the multivariable model, while cytogenetic risk group was borderline statistically significant. In the subgroup study, CR rates were 0% and 20% for patients exposed to LDAC- and HMA-based regimens, respectively. Conclusions: A greater proportion of patients received first-line treatment with HMA over time, which was associated with lower risk of death. However, most patients treated with HMA became refractory to HMA treatment, highlighting the need for optimized treatment strategies.

MM-429: Impact of Prolonged Lenalidomide Maintenance (≥3 years) and Outcomes in Patients with Multiple Myeloma Post-Autologous Stem Cell Transplant

Context Lenalidomide maintenance therapy after autologous stem cell transplantation (ASCT) is standard of care for patients with multiple myeloma (MM). However, optimal duration of maintenance, as well as factors predicting outcomes, need further evaluation. Objective To determine impact of duration of therapy and identify factors affecting outcome of lenalidomide maintenance. Design Retrospective study of consecutive patients with MM seen at Mayo Clinic, Rochester between 1/1/2005 and 12/31/2016. Patients or Other Participants Two hundred thirteen patients treated with lenalidomide-based maintenance post-ASCT were included. Main Outcomes Measures Progression-free survival (PFS), overall survival (OS), and impact of duration of therapy on PFS and OS. Results The median follow-up was 5.4 (95% CI: 4.9, 5.9) years from diagnosis. Median age at initiation of maintenance was 60 years (range: 35–76). Cytogenetics data were available in 202 (95%) patients; 31% (63/203) harbored high-risk cytogenetics based on the mSMART 3.0 criteria. The median PFS was 4 years (95% CI: 3.4, 4.5) from diagnosis of MM and 3 years (95% CI: 2.6, 3.5) from start of maintenance; median OS was not reached from diagnosis of MM (5-year OS: 77%). Excluding patients progressing within 3 years of starting maintenance (n=65), patients receiving ≥3 years of maintenance (n=48) had superior 5-year OS of 100% versus 88% in patients who received Conclusions Maintenance therapy with lenalidomide is well tolerated, and a longer duration (≥3 years) is associated with improvement in OS, irrespective of cytogenetic risk group and ISS stage.

The Degree and Effect Of Weight Loss In Acute Myeloid Leukemia Patients Receiving Induction and Post-Remission Chemotherapy

▪ IntroductionInduction and post-remission chemotherapy for acute myeloid leukemia (AML) is an intensive regimen with significant toxicities performed almost exclusively in inpatient or closely monitored outpatient settings. Extreme weight loss is associated with poor outcomes in cancer. We studied whether treated AML patients (pts) lose a substantial amount of weight and whether weight loss affects overall survival (OS). MethodsAdult pts diagnosed with AML at the Cleveland Clinic from 08/08 - 11/12 were included. All pts completed intensive induction chemotherapy with 7+3 (cytarabine and anthracycline – daunorubicin, idarubicin, or mitoxantrone) as first-line therapy. Pts must have achieved complete remission (CR) by first-line induction or day 14 re-induction chemotherapy. Previously treated pts or those with relapsed or refractory disease were excluded. Co-morbidities and AML disease characteristics were assessed, in addition to weight and body-mass index (BMI) at baseline and throughout AML treatment course until disease relapse, stem cell transplantation (SCT), or loss-to-follow-up/death. The primary endpoints were change in BMI relative to completion of post-remission therapy (PRT), OS, and event-free survival (EFS). OS and EFS were measured from completion of PRT to the date of death (OS) and relapse or need for SCT (EFS). To assess impact of weight recovery on OS and EFS separate linear regression models were fit to each pt to determine rate and direction of change during the first 3 months following the completion of PRT. Pts whose fitted regression lines had slopes>0 were considered to have positive weight trajectories; pts with slopes<0, negative trajectories. Group comparisons were made using the Wilcoxon signed-rank test, logrank test, and proportional hazards models. ResultsOf 126 AML pts who met the inclusion criteria, 43% (n=54) were male and the median age at treatment start was 54 years (range 18-77). Disease characteristics were: acute promyelocytic leukemia 11% (n=14), other AML 89% (n=112); de novo 75% (n=94), secondary 24% (n=31); cytogenetic risk group - favorable 23% (n=29), intermediate 47% (n=59), unfavorable 21% (n=27), unknown 9% (n=11). Co-morbidities potentially impacting BMI and outcome included diabetes (11%), hypertension (42%), hyperlipidemia (28%), alcohol use (65%), use of steroids (13%) or oral contraceptives (16%). Median weight at the start of therapy was 84.9kg (range 37-159.5) and BMI was 29.6 (range 17.6-57.8). BMI groups included normal (18.5-24.9, 26%), overweight-moderately obese (>25-35, 54%), severely obese (>35, 20%). From the start of treatment, median weight loss was: 2% (range -21-53%, p=0.0001) at day 14; 6% (range -19-22%, p<0.0001) at time of CR determination; 4% (range -23-38%, p<0.0001) at end of PRT. With the exception of diabetes (time of CR, p=0.06) and alcohol use (time of CR and end of PRT, p=0.05 in both cases), none of the clinical or demographic factors examined impacted weight loss. In total, 29% of pts (n=37) had >10% weight loss at the completion of PRT, representing an absolute loss of 5.9-20.6kg; 40% of pts (n=50) had a loss<10%, and 31% of pts (n=39) had no change or weight gain. In the group with >10% loss, median time to recovery of >95% pre-treatment weight was 7 months; 11% of pts (n=4) exceeded their pre-treatment weight by >10%. Only age (p=0.06) was associated with weight recovery time, with younger pts recovering weight faster (Figure 1). 60% of pts (n=73) had disease progression and 36% of pts (n=44) had died; estimated EFS and OS are 10.1 (95% CI 6.6-14.7) and 28.2 months (95% CI 17.1-46.4), respectively. The degree of weight loss following completion of PRT was not associated with EFS (p=0.79) or OS (p=0.82). However, there was some indication that pts with positive weight trajectories had longer EFS than pts with negative trajectories, p=0.07 (Figure 2); OS was not impacted significantly (p=0.26). ConclusionAML pts achieving CR with induction therapy experience a median 6% weight loss from start of therapy, but recover by 7 months (median). Those with diabetes or alcohol use lose more weight. Weight changes were not associated with survival; however, there was some suggestion that pts who began to gain weight once PRT was completed had longer EFS than pts whose weight continued to decline. These data can be used to frame pt expectations about weight fluctuations going through AML treatment. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Downregulation Of The Wnt Inhibitor CXXC5 Predicts a Better Prognosis In Acute Myeloid Leukemia

▪Different CXXC zinc finger proteins like MLL, DNMT1 and TET1 have been identified to play a role in leukemia development. The CXXC family member CXXC5 is located on 5q31, a region recurrently deleted in acute myeloid leukemia (AML), suggesting that inactivation of CXXC5 might be involved in leukemogenesis. CXXC5 has previously been shown to exert tumor suppressor functions in solid tumor cells and to negatively regulate Wnt signaling, a known pro-survival pathway in leukemia. Here, we investigated prognostic and biological implications of CXXC5expression in AML.CXXC5 mRNA expression was determined by real time quantitative PCR in pretreatment bone marrow samples of 186 AML patients enrolled on the Medical Research Council (MRC) AML15 and UK National Cancer Research Institute (NCRI) AML17 trials. We found downregulation of CXXC5 in AML compared to healthy controls, particularly in cases with del(5q)/-5, MLL rearrangements and t(8;21). To investigate CXXC5-associated gene expression, microarray data from 351 normal karyotype AML derived from the Microarray Innovations in LEukemia study and 529 unselected AML patients treated in Dutch-Belgian-Swiss Hemato-Oncology Cooperative Group (HOVON/SAKK) trials were analyzed. CXXC5 was associated with expression of several genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1), indicating that alteration of CXXC5 expression is a downstream effect of different leukemic pathways. Data from the HOVON/SAKK cohort (median age 46 years (range 15-77) was further used to perform outcome analyses according to microarray-based CXXC5 expression. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P=0.007) and a better overall survival (OS: 46% vs 28%; P<0.001) and event-free survival (EFS: 36% vs 21%; P<0.001) at 5 years. This was of independent significance in multivariate analyses after adjustment for age, white blood cell count, cytogenetic risk group, FLT3-ITD status, biallelic CEBPA mutations, as well as mutations of NPM1, DNMT3A and ASXL1.DNA sequencing of CXXC5 exons 1-3 on 84 AML cases revealed no mutations, suggesting that CXXC5 is predominantly inactivated by gene regulatory mechanisms in AML. Pyrosequencing analysis showed that lower expression of CXXC5 in AML samples was correlated with hypermethylation within the promoter region. Treatment of NB4 and U937 cell lines with 5-Aza-2´-deoxycytidine led to demethylation of this region and induction of CXXC5 at the mRNA and protein level.Functional analyses confirmed Wnt inhibitor function of CXXC5 in leukemic cells. K562 cells overexpressing pEGFP-C2-CXXC5 showed impaired upregulation of active β-catenin protein, decreased upregulation of Wnt target genes Axin2 and Survivin, as well as decreased Wnt reporter activity after Wnt3a stimulation. In addition, we found evidence for involvement of CXXC5 in the DNA damage-induced p53 response in leukemia. Knockdown of CXXC5in OCI-AML3 cells harboring wildtype p53 led to attenuated p53 upregulation and cell cycle arrest after γ-irradiation.In summary, we have identified CXXC5 as a novel independent prognostic factor in AML. Our data suggest a tumor suppressor function of CXXC5 in AML and association of the gene with different leukemic pathways. These functional and prognostic implications build the framework for further investigating the role of CXXC5 in leukemia. AML patients with downregulation of CXXC5 might be candidates for evaluation of Wnt inhibition and cases with epigenetically silenced CXXC5 expression may particularly benefit from demethylating agents. Disclosures:Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership.

Cytogenetic risk groups for childhood acute myeloid leukemia based on survival analysis in a cancer referral hospital from Perú

ResumenIntroducción. La leucemia mieloide aguda es una neoplasia heterogénea caracterizada por la proliferación de células mieloides inmaduras. El análisis citogenético ha revelado la presencia de aberraciones cromosómicas de importancia en el pronóstico del paciente.Objetivo. Determinar los grupos de riesgo citogenético de pacientes pediátricos con leucemia mieloide aguda a partir de la supervivencia global.Materiales y métodos. Se hizo un estudio observacional de corte transversal. Se incluyeron los registros clínicos de los pacientes pediátricos con diagnóstico de leucemia mieloide aguda de novo admitidos en el Instituto Nacional de Enfermedades Neoplásicas entre el 2001 y el 2011 y sometidos a análisis citogenético de médula ósea. Los grupos de riesgo citogenético se establecieron según los criterios del Medical Research Council. Las curvas de supervivencia global se elaboraron con el método de Kaplan-Meier y se compararon mediante la prueba de Mantel-Cox y una regresión de Cox, utilizando el programa R, versión 3.3.2.Resultados. Se incluyeron 130 pacientes, 68 varones (52,3%) y 62 mujeres (47,7%), mayoritariamente del subtipo M2 (33%). La edad promedio fue de 7,7 (rango de 0 a 15 años). Se observaron aberraciones cromosómicas en el 60,8% y la más frecuente fue la traslocación t(8;21). Según el análisis de supervivencia global, se observaron dos grupos de riesgo citogenético: favorable y desfavorable.Conclusión. Se determinaron dos grupos de riesgo citogenético: alto (o desfavorable) y estándar (o favorable).

Prospective Study of Acute Myeloid Leukemia (AML) Clinical Epidemiology and Cytogenetic Risk Group in Older Adults in the ECOG-ACRIN E2906 Clinical Trial: The Acute Leukemia Epidemiology, Survival and Endpoints (ALESE) Study

Prospective Study of Acute Myeloid Leukemia (AML) Clinical Epidemiology and Cytogenetic Risk Group in Older Adults in the ECOG-ACRIN E2906 Clinical Trial: The Acute Leukemia Epidemiology, Survival and Endpoints (ALESE) Study

Over-Expression of ERG Predicts Poor Outcome in Acute Myeloid Leukemia

Introduction: Acute myeloid leukemia (AML) treatment aims at the eradication of all leukemic cells to achieve cure. Available treatments produce complete remission (CR) in up-to 80% of patients. However, ~60% of them will relapse. Various prognostic factors such as baseline white blood cell count (WBC), cytogenetics and mutations of FLT3 , NPM1 , CEBPA have been shown to affect the survival. The high expression of brain and acute leukemia cytoplasmic (BAALC) and ETS- related gene (ERG) has been associated with poor prognosis but due to limited prospective studies, their role as prognostic factors is still unclear. We aim to substantiate the prognostic value of BAALC and ERG expression in adult AML patients.Materials and methods: All patients included in this prospective study (N=149) between March 2012 and February 2015 underwent marrow for following investigations: (i) Cytogenetic analyses- by standard techniques of chromosome banding and FISH (ii) Mutation profiling of NPM1 , FLT3 -ITD and CEBPA by capillary electrophoresis and direct DNA sequencing. Long range PCR was done to detect KMT2A-PTD (MLL -PTD) (iii) BAALC and ERG expressions by quantitative real time PCR assays. Abelson (ABL ) gene was used as an internal control. According to the baseline median values of BAALC and ERG expression, patients were divided into high and low expressers.Patients received standard induction chemotherapy with daunorubicin 60 mg/m2 for 3 days and cytosine arabinoside 100 mg/m2 for 7 days. Marrow was done 21-28 days after start of chemotherapy. If marrow was in remission, then patients received 3 courses of consolidation therapy with 12-18 gm/m2 of cytosine arabinoside (HiDAC). Patients underwent allogeneic transplant if feasible according to molecular and cytogenetic risk.Statistical analysis was done using SPSS-21. Overall survival (OS) was defined as time from start of induction therapy to time to last follow up or death. Relapse free survival (RFS) was defined as time from achieving CR to time to relapse, death or last follow up if in CR. Results of the expression studies, cytogenetic and molecular groups were analyzed for their impact on OS and RFS. Variables known to have prognostic implications such as baseline WBC, cytogenetics risk groups and molecular markers were grouped according to high/low BAALC and ERG expressers. Comparison of these prognostic factors within high/low expressers was carried out by Chi-square method. Survival was calculated by Kaplan-Meier method and prognostic factors were compared by log-rank test. Multivariate analysis was carried out using the Cox proportional hazards model. All covariates whose univariate models reflected a P value less than 0.2 were considered for inclusion in the model.Results: A total of 149 patients were accrued. The median age of the cohort was 27 years (range 15-58 ) with male predominance (M:F =98:51). Of 149 patients, 105 achieved CR after 1 or 2 cycles of chemotherapy. Twenty-seven patients were refractory of which 18 were lost to follow up and hence excluded from OS analysis. Seventeen patients died during induction. The OS of 131 patients was 36.5% at 2 years. The OS and RFS of 105 patients who achieved CR was 54% and 43.8% respectively. The median value (60 BAALC copies /ABL and 58 ERG copies /ABL ) was used to distinguish high expressers from low expressers. At baseline, copy numbers of 149 patients ranged from 11.58 to 242.23 for BAALC and 16.2 to 328.2 for ERG. For BAALC , 69/149(46.3%) were high expressers as compared to 80/149 (53.7%) as low expressers. Concerning ERG , 76/149(51%) were high and 73/149(49%) were low expressers. The OS and RFS of high BAALC versus low BAALC expressers at 2 years was 13.8% vs 59.8% (p<0001) and 17.6% vs 72.1% (p<0001) respectively. Similarly OS and RFS of high ERG vs low ERG expressers at 2 years was 5.3% vs 66.4% (p<0001) and 5% vs 71.2% (p<0001) respectively (Figure).The median baseline WBC count was significantly higher in high BAALC/ERG expressers. There was no difference in distribution of FLT3 -ITD, NPM1, CEBPA, MLL -PTD and cytogenetic risk groups in high versus low BAALC and ERG expressers. Multivariate analysis showed that ERG overexpression was only prognostic factor affecting OS and RFS compared to high BAALC expressers, MLL -PTD mutation, cytogenetic risk groups and baseline WBC.Conclusion: This study shows that high ERG expression adversely affects prognosis of AML patients independent of other well known prognostic factors [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Omacetaxine Mepesuccinate for Patients with Higher-Risk MDS and CMML after Failure of Hypomethylating Agents: A Phase II Trial

Background: The outcome of patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor with a median survival of 4-6 months. Omacetaxine mepesuccinate (OM) has been shown to be safe and effective in acute myeloid leukemia, including in pts who progressed from MDS. We designed a phase II trial to evaluate the safety and efficacy of OM in pts with MDS and chronic myelomonocytic leukemia (CMML) after HMA failure.Methods: Adult pts with MDS or CMML who had not responded to, progressed on, or relapsed after HMA therapy were eligible for this study. Pts were required to be intermediate-2- or high-risk by the International Prognostic Scoring System (IPSS) or be classified as RAEB-1 (5-9% BM blasts), RAEB-2 (10-19% BM blasts) or CMML (5-19% BM blasts). Pts received OM 1.25 mg/m2 SQ every 12 hours x 3 days on a 28-day cycle. The primary efficacy outcomes were overall survival (OS) and the overall response rate (ORR). Secondary outcomes included the remission duration, relapse-free survival (RFS), and the safety of the regimen.Results: Between 6/2015 and 6/2017, 35 pts have been treated. Baseline characteristics are shown in Table 1. The median age of the cohort was 73 years (range, 61-86 years). The median BM blasts was 10% (range, 2-19%) and 15 pts (43%) had poor-risk karyotype. IPSS risk group was intermediate-1 in 8 pts (23%), intermediate-2 in 13 (57%), and high in 7 (20%). 27 pts (77%) were either high risk (n=10) or very high risk (n=17) by IPSS-R. Among 33 pts who underwent comprehensive mutation profiling, 29 (88%) had at least one mutation identified. The most frequently identified mutations were RUNX1 in 10 pts (30%), TP53 in 10 (30%), ASXL1 in 6 (18%) and TET2 in 4 (12%).The median duration of follow-up was 17 months (range, 2-24 months), and the median number of cycles of OM received was 2 (range, 1-18). The ORR was 34%; 3 pts achieved CRp and 9 pts achieved CRi as best response. The median number of cycles to best response was 2 (range, 1-4 cycles). The response rates for pts with MDS and CMML were 41% and 0%, respectively (P=0.02). Responses were seen across cytogenetic risk groups: 5 responders were diploid, 4 had either complex cytogenetics or monosomy 7, and 3 had miscellaneous cytogenetic abnormalities. The response rate for pts with diploid and adverse-risk cytogenetics were 56% (5/9) and 27% (4/15), respectively (P=0.16).Of the 12 responders, 4 remain on study, 5 relapsed, 2 died while in response, and 1 was lost to follow-up. To date, 24 pts (69%) have died. The median OS was 7.6 months, and the 1-year OS rate was 22% (Figure 1). The median RFS was 2.9 months, and the 1-year RFS rate was 28%. Two pts have had ongoing response ≥12 months (15.6 and 19.8 months), both of whom had MDS with diploid cytogenetics.Treatment was overall well-tolerated. Among 26 pts who have received ≥2 cycles of OM, 2 (8%) required dose reduction during subsequent cycles. Most adverse events were grade 1-2; grade ≥3 adverse events occurred in 8 pts (23%). The most frequent non-hematologic adverse events were fatigue in 17 pts (49%), nausea in 12 (34%), mouth sores or mucositis in 6 (17%), infection in 5 (14%) and edema in 5 (14%). The 30-day and 60-day mortality rates were 11% and 14%, respectively.Conclusions: In pts with MDS and CMML who previously failed HMA therapy, OM was safe and resulted in an ORR of 34%. Responses were seen across cytogenetic risk groups but were restricted to patients with MDS. [Display omitted] DisclosuresTakahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Bose:Incyte Corporation: Honoraria. Cortes:BMS: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.

Molecular Epidemiology of Acute Myeloid Leukemia (AML): Novel Association of Clinical Epidemiologic Exposures with Unique Mutation Groups on Exome Sequencing of Leukemia DNA in the Mayo Clinic AML Epidemiology Cohort

Background: Clinical epidemiologic risk factors associated with leukemia development are prevalent, and can be identified in over 90% of AML patients. We previously demonstrated an association of clinical exposures with cytogenetic risk group and outcome after therapy, but the molecular impact of such exposures is unclear, and specifically it is not known whether specific epidemiologic exposures are associated with unique genetic lesions. We therefore performed Exome Sequencing in 98 patients from our clinical epidemiology cohort to determine whether there was an association of clinically relevant AML risk factors and exposures with unique deleterious non-synonymous (nonsyn.) mutations.Methods: The Mayo Clinic AML Epidemiology cohort comprises a highly annotated series of n=295 unselected and consecutive patients diagnosed and treated at Mayo Clinic Florida & Arizona [Cancer Epidemiol 39:1084, 2015]. We obtained AML DNA from remnant diagnostic cytogenetic pellets identified in 98 patients in the cohort, and performed Exome Sequencing [ExSeq] using standard techniques. The ~100 million paired-end 100bp reads from each sample were mapped to human genome build hg19 using BWA-MEM 1. The single nucleotide variants (SNVs) and small INDELs in the exome capture regions were identified using Mayo Clinic in-house developed analytic pipeline GenomeGPS 4.0.1 following Broad GATK 2 variant discovery best practices of alignment, realignment and recalibration, haplotype caller, and multi-sample joint genotyping. The variants passed the GATK's Variant Quality Score Recalibration (VQSR) quality control were kept. Since no patient matched normal were sequenced, SNVs and INDELs were filtered using both germline whole exome and whole genome sequencing of ~1200 Mayo Clinic Biobank samples and the public germline variant databases of 1000 genome project, 6500 individuals sequenced in the exome sequencing project (ESP), and HapMap phase 3. The remaining variants were annotated using ANNOVAR 3, and potential functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. We evaluated the association of unique mutations occurring in 10 or more patients and in TP53, and also gene categories according to algorithm of Lindsley et al (Blood 125:1367, 2015) with relevant clinical and epidemiology exposures identified in our prior analysis. Risk factors and exposures were compared between patients with and without a mutation in different genes of interest using Fisher's exact test.Results: The read quality was excellent, and results from 97 evaluable samples were included in analysis. Results are noted in Table. We found a strong and significant association of prior history of immunosuppressive therapy (IST) or solid organ transplantation (SOT) with RUNX1 mutation (p=0.0001), and of regular Statin use with ASXL1 mutation (p=0.008). Statin use was also associated with mutations in genes involved in DNA methylation (p=0.036) and in Chromatin Modifier genes (p=0.049). We identified a novel inverse association of obesity - the most prevalent AML risk factor - with spliceosome mutation (p=0.010), and of IST/SOT with mutations in Myeloid Transcription Factors (TF, p=0.015) and Activated Signaling pathways [RAS, FLT3, KIT, CBL, NF1] (p=0.026). We confirm the association of secondary AML [sAML] with spliceosome mutation (p=0.018), observed as expected most strongly for Antecedent Hematologic Disorder (p=0.008, not shown). Other borderline associations (p≤0.10) are noted in Table. We did not identify any association of family history [FHx] of hematologic malignancy or of smoking [TOB] with unique mutations, nor did we identify clinical exposures associated with TP53 mutation.Conclusion: For the first time (apart from sAML) we have identified a unique leukemia genotype associated with some common clinical and epidemiologic exposures. Some mutations groups (Cohesin, TP53) were not associated with any clinical exposures, suggesting alternate mechanisms of leukemogenesis. ExSeq was for the first time successfully performed on archived diagnostic cytogenetic cell pellets, we believe a novel source of leukemia DNA. These results will guide a planned prospective study to determine frequency and mechanism of leukemogenesis after exposures, and development of strategies for prediction of leukemia risk and ultimately prevention. [Display omitted] DisclosuresCerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering .