Antecedent Hematologic Disease Research Articles

Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification

Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.

Abstract 6612: Data-driven hallmarks of cancer as a new paradigm for precision medicine: multi-omics and functional profiling in acute myeloid leukemia

Abstract The cancer hallmark concept defines biological properties that play a key role in cancer development and progression. The hallmarks reflect generic properties across all cancer types, and are not directly quantifiable nor applicable in cancer diagnostics. Here, we applied a data-driven approach to identify quantifiable hallmarks to be used as a basis for precision cancer medicine (PCM) in Acute Myeloid Leukemia (AML). We applied deep exome, transcriptome, DNA methylation and proteome profiling as well as ex-vivo functional testing of 525 drugs to 118 AML patient samples. Unsupervised multi-omic dimensionality reduction defined 11 independent axes of biological variability that we interpreted to reflect data-driven hallmarks (DDHM) of AML. Each DDHM integrates and ranks different data types and features, pinpointing those molecular features that were most informative for each hallmark. We calculated values for the 11 DDHM for each patient, constructing a DDHM-based precision medicine approach for AML diagnosis and therapy assignment. Most DDHMs were driven by other data types than genomics. For several DDHMs, different cytogenetic and mutational drivers converge on the same hallmarks and specific drug vulnerabilities. We also see how DDHM predictors of poor prognosis and high-risk AML are distinct from those that dictate specific drug response vulnerabilities. DDHM 2 reflected the cell differentiation path leading towards resistance to BH3 mimetics, ACK-inhibitors, and anthracyclines, and sensitivity to MEK inhibitors and TLR8 agonists. DDHM 2 derived a strong impact from protein expression of GATA2, MLLT11, DNMT3B and from RNA expression of WT1 and SOX4 as well as from multiple markers of different monocytic subtypes. DDHM 5 depicted cell cycle regulation and the Megakaryocytic-erythrocyte progenitor cell state that was enriched in AML patients with antecedent hematological disease. Interestingly, DDHM5 was linked to the sensitivity to purine analogs and vinca alkaloids. Moreover, DDHMs 1 and 8 captured clinical risk groups, prognosis, and responsiveness to hypomethylating agents. These DDHMs also revealed the phenotypic and functional biology that distinguished patients with high versus low FLT3-ITD mutant allele frequency. Validation of the DDHMs is realized through profiling and analysis of prospective AML samples, AML cell lines and previously published datasets. In summary, we present a data-driven approach for defining hallmarks in AML. The application of the DDHMs in AML provides a new paradigm for PCM and an opportunity for combinatorial therapeutic targeting. Each patient is characterized by a combination of independent and potentially druggable hallmarks, as opposed to traditional stratification in PCM, where each patient is assigned to one specific subgroup defined by genetic or other biomarkers. Citation Format: Tom Erkers, Nona Struyf, Tojo James, Francesco Marabita, Mattias Vesterlund, Nghia Vu, Cornelia Arnroth, Albin Österroos, Anna Bohlin, Sofia Bengtzén, Matthias Stahl, Rozbeh Jafari, Lukas Orre, Yudi Pawitan, Brinton Seashore-Ludlow, Janne Lehtiö, Sören Lehmann, Päivi Östling, Olli Kallioniemi. Data-driven hallmarks of cancer as a new paradigm for precision medicine: multi-omics and functional profiling in acute myeloid leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6612.

Prognostic Impact of Secondary Versus De Novo Ontogeny in Acute Myeloid Leukemia (AML) Is Predominantly Accounted for By the European Leukemianet (ELN) 2022 Risk Classification

Background: Compared to de novo AML (dnAML), secondary AML (sAML) is recognized to have worse prognosis regardless of whether it stems from antecedent hematologic disease (AHD) or prior chemoradiation exposure (therapy-related, tAML). This classification is frequently used in determining eligibility for clinical trials or therapies. Additionally, clinicians may consider patients as sAML based on history of antecedent blood count abnormalities in the absence of a pathologically proven AHD. However, the poor prognosis of sAML may reflect the adverse risk genetics that often accompany this label as opposed to the historical features themselves: the European LeukemiaNet (ELN) 2022 risk classification newly incorporates secondary-like genetic features in its adverse risk group, and TP53 mutation underlies the adverse prognosis of many tAML cases. Herein, we evaluated whether AHD, therapy-relatedness, or antecedent blood count abnormalities were independently prognostic after accounting for ELN 2022 risk category and TP53 mutation at time of AML presentation. Methods: Clinical, histopathologic, cytogenetic, and molecular genetic data were collected on 735 adults with newly diagnosed AML from Johns Hopkins Hospital (JHH; Baltimore, MD) and Massachusetts General Hospital (MGH; Boston, MA). Per WHO criteria, post-AHD sAML cases were identified by prior pathologic diagnosis of AHD (e.g., myelodysplastic syndrome or myeloproliferative neoplasm). tAML cases were identified by history of prior chemoradiation exposure. dnAML cases were evaluated for previous abnormal blood counts at least 28 days and up to 2 years prior to AML diagnosis. AML therapies were categorized as either with curative intent (intense therapies, e.g., 7+3) or not (less intense therapies, e.g., hypomethylating agent/venetoclax therapy or supportive care). Wilcoxon rank-sum and Fisher's exact tests were used to compare groups. Uni- and multivariable Cox models evaluated associations between overall survival (OS) and covariates: age, performance status (PS; ECOG 0-1 as good vs 2-4 as poor), therapy type, ELN 2022 risk group, TP53 mutation, prior abnormal counts, and hematopoietic stem cell transplant status (time-dependent). Results: Of the 735 patients in the cohort (388 from JHH, 347 from MGH), 410 (56%) had dnAML, 202 (27%) had sAML from AHD, and 123 (17%) had tAML. Of the dnAML patients, 86 previously had normal and 154 had abnormal prior blood counts documented; antecedent blood counts were not available in the remaining patients. AHD and tAML patients were older than dnAML patients (median age 68 and 67 versus 62 years respectively, P<0.001) and more often ELN adverse compared to dnAML (83% and 69% versus 44% respectively, P <0.001). Fewer AHD and tAML patients received curative intent treatment versus dnAML (36% and 43% versus 71% respectively, P<0.001). On univariate analysis, dnAML patients had longer OS than AHD and tAML patients; OS of dnAML with abnormal prior counts fell between dnAML with normal prior counts, AHD, and tAML patients (Figure 1). On multivariable analysis controlling for age, PS, ELN risk, TP53, therapy class, and transplant, dnAML with abnormal prior counts lost prognostic significance (hazard ratio [HR] = 1.17 [reference = dnAML with normal prior counts]; 95% confidence interval [CI] 0.79-1.73, P=0.44). In a subsequent multivariable analysis, AHD and tAML were associated with a poorer prognosis compared to dnAML (regardless of prior counts) after controlling for the other model covariates including ELN risk, although the HRs were attenuated from the univariate model (Table 1; univariate vs multivariable: AHD HR=2.63, 95% CI 1.84-3.76 vs 1.33, 95% CI 1.06-1.67; tAML HR= 2.67, 95% CI 1.83-3.90 vs 1.29, 95% CI 1.00-1.66). Conclusions: In this multicenter cohort, antecedent blood counts did not provide independent prognostic information for de novo AML patients after accounting for ELN 2022 genetic risk and TP53 mutation status. Nonetheless, AHD/tAML maintained prognostic association with shorter OS in the multivariable model, though with reduced effect size by hazard ratio. These findings suggest there remains a role for using secondary vs de novo ontogeny to clinically risk stratify patients, but also emphasizes the greater role genetics (i.e., ELN) should have in risk assessment and clinical trial eligibility in newly diagnosed AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of induction chemotherapy with intermediate-dosed cytarabine and subsequent allogeneic stem cell transplantation on the outcome of high-risk acute myeloid leukemia

BackgroundAcute myeloid leukemia (AML) with antecedent hematological disease (s-AML) and treatment-related AML (t-AML) predicts poor prognosis. Intensive treatment protocols of those high-risk patients should consider allogeneic stem cell transplantation (allo-HSCT) in first complete remission (CR). Despite allo-HSCT, relapse rate remains high. Induction chemotherapy with liposomal cytarabine and daunorubicin (CPX-351) has been approved for patients with AML with myeloid-related changes (AML-MRC) or t-AML based on improved survival and remission rates compared to standard 7 + 3 induction.Patients and methods110 patients with newly diagnosed s-AML or t-AML at a university hospital were analyzed retrospectively. Median age was 62 years (24–77 years). A total of 65 patients with s-AML after MDS (59%) and 23 patients (20.9%) with t-AML were included. Induction chemotherapy consisted of intermediate-dosed cytarabine (ID-AraC) in combination with idarubicin (patients up to 60 years) or mitoxantrone (patients over 60 years). In patients subsequently undergoing allo-HSCT, reduced conditioning regimens (RIC) were applied prior to transplantation in 47 of 62 patients (76%).ResultsInduction chemotherapy with ID-AraC resulted in an overall response rate of 83% including complete remission (CR/CRi) in 69 patients (63%) with a low rate of early death (2.7%). Most relevant non-hematologic toxicity consisted of infectious complications including sepsis with need of intensive care treatment in five patients (4.5%) and proven or probable invasive fungal disease in eight patients (7.2%). Relapse-free survival (RFS), event-free survival (EFS) and overall survival (OS) of the whole cohort were 19 months (0–167), 10 months (0–234) and 15 months (0–234), respectively (p < 0.0001). A significant improvement of OS was observed in patients who underwent allo-HSCT compared to those without subsequent allo-HSCT: 9 vs. 46 months, p < 0.0001. Rate of transplantation-related mortality (TRM) in the early phase post allo-HSCT was low (0.9% at day 30 and 1.8% at day 90, respectively). RIC conditioning results in OS rate of 60% after 60 months post allo-HSCT (median OS not reached).ConclusionS-AML and t-AML patients receiving induction chemotherapy with intermediate-dosed cytarabine showed satisfactory response rate and consolidation therapy with allo-HSCT after full or reduced-intensity conditioning further improved survival in these patients with similar outcome as reported for CPX-351.

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Hypomethylating Agents Versus Intensive Chemotherapy in Elderly Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

▪BackgroundAcute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. Optimal frontline therapy for elderly AML patients remains controversial. Intensive chemotherapy (IC) is often favored in those AML patients who present with leukocytosis (P-AML), yet the evidence to support this practice as opposed to lower intensity therapy is scarce. We aimed to investigate the outcomes of older patients with P-AML based on treatment choice of intensive chemotherapy (IC) vs hypomethylating agents (HMA).MethodsWe retrospectively analyzed 983 elderly AML patients (age ≥ 70 years) treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to HMA for non-AML diagnoses were excluded. We focused on P-AML patients, defined as baseline WBC ≥ 10x109/L, who received initial therapy with either: intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent) or hypomethylating agents (HMA) (azacitidine (AZA) or decitabine (DEC)). Age, type of AML, history of antecedent hematologic disease, cytogenetics (per European LeukemiaNet (ELN) criteria), Eastern Cooperative Oncology Group (ECOG) performance status, Charlson comorbidity Index (CCI), complete blood counts and myeloblast percentage at time of diagnosis were obtained for each patient. Kaplan-Meier analysis was performed to calculate overall survival (OS) and the log-rank test was used to determine significance where a p-value of 0.05 was defined as significant. Fisher's exact t-test, hazard ratios (HR) and confidence interval (CI) were calculated using GraphPad Prism v7.03. Univariate and multivariate analysis for the baseline characteristics and type of therapy were performed using SPSS v24.0 to determine prognostic impact.ResultsWithin the entire cohort of older AML patients, we identified 156 who were treated with either HMA (n=41) or IC (n=115). Baseline characteristics of these patients are described in Figure 1A. Significant baseline differences in age, hemoglobin, WBC, ELN cytogenetic category, marrow blast %, and CCI score were observed between the HMA and IC groups. Most notably, the HMA group were older (median age 77 yrs vs 74 yrs, p=0.0037), had a higher incidence of poor-risk cytogenetics (36.6% vs 7%), and were more likely to have CCI score ≥ 3 (29.3% vs 8.7%).Median time of initial treatment was 4.3 months (range: 0.10-70.0 months) in the HMA group compared to 0.5 months (range: 0.33-1.90months) in the IC group. Median OS of the entire group was 7.85 mo. Median OS in the HMA-treated patients was superior to IC treated patients (13.7 mo vs. 5.1 mo, HR 0.63, 95% CI 0.443 - 0.886, p=0.0082) (Figure 1B). The 12 month survival rate was 55.0% in the HMA group and 31.0% in the IC group (p=0.0082). Fifty-two (33%) patients achieved CR/CRi. There was no difference in CR/CRi rates between HMA or IC treated cohorts (30.0% vs. 34.8%, p=0.6983). Rate of relapse upon achievement of CR/CRi was not statistically significant between HMA and IC cohort (41.7% vs. 62.5%, p=0.3181). The 30-day mortality rate was lower in the HMA group compared to the IC group (7.3% vs 24.4%, p=0.0217).Univariate analysis identified treatment type (p<0.0001), cytogenetic risk category (p <0.0001), and ECOG performance status (p<0.0001) as significant prognostic factors for OS. Multivariate analysis identified IC treatment (HR 2.01, 95% CI 1.24-3.26, p=0.005) and poor ECOG performance status (HR 4.30, 95% CI 1.182-15.659, p=0.027) as independent negative predictors of OS.ConclusionsElderly patients (age ≥ 70) with proliferative AML appear to achieve a survival advantage with HMA-based frontline therapy compared to IC, despite a disproportionately higher incidence of traditionally adverse prognostic features (poor-risk cytogenetics, high CCI score) in the HMA group. The reasons for this observation are unclear, but could relate to a higher early death rate with IC or biologic/molecular features that induce greater sensitivity to HMAs, which should be studied in future analyses. Although this study was limited by small size and retrospective nature, our findings cast doubt on the notion that intensive therapy should be the standard frontline approach in elderly patients proliferative/high WBC AML. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Lancet:Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy; Pfizer: Other: Institutional research funding.

Outcomes in Older Adults (age ≥ 70) with Acute Myeloid Leukemia Based on Choice of Frontline Treatment for Proliferative or Non-Proliferative Phenotype

IntroductionAcute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. The optimal selection of frontline therapy remains controversial, with intensive chemotherapy (IC) often favored in AML patients who present with a proliferative phenotype (P-AML) compared to a non-proliferative phenotype (NP-AML), yet evidence to support this approach is lacking. We aimed to investigate the outcomes of older AML patients based on treatment choices including intensive chemotherapy (IC), hypomethylating agents (HMA) and low intensity therapy (LI) (excluding HMAs), stratified on the basis of a proliferative and non-proliferative phenotype.MethodsWe retrospectively analyzed clinical and laboratory parameters along with treatment outcomes in 983 elderly AML patients treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to hypomethylating agents for non-AML diagnoses were excluded. Patients were placed into one of four cohorts based on the type of frontline therapy received: Intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent); hypomethylating agents (HMA) (azacitadine (AZA) or decitabine (DEC)); low intensity therapy (LI) (defined as low-dose cytarabine or similar agent excluding HMAs); or supportive care (SC) (including hydroxyurea). P-AML was defined as presence of ≥30% bone marrow (BM) myeloblasts, whereas NP-AML was defined as 20%-29% BM myeloblasts at diagnosis. Age, type of AML, history of antecedent hematologic disease, cytogenetics, ECOG performance status, Charlson comorbidity Index, complete blood counts and myeloblast percentage at diagnosis were compared for each patient. Kaplan-Meier analysis was performed to calculate overall survival and the log-rank test was used to determine significance where a p-value of <0.05 was defined as significant.ResultsOf the 983 patients, 718 patients had data regarding BM blast percentage at diagnosis without previous exposure to HMA who were included in the analyses. Of these, 479 (66.71%) were classified as P-AML and 239 (33.29%) as NP-AML. Baseline characteristics are described in Figure 1A. Overall survival (OS) of the entire cohort was 8.0 months (mo). No significant difference was noted in OS between NP-AML and P-AML (8.9 vs. 7.7mo respectively, p=0.1741). The analysis based on treatment modality with focus on HMA and IC revealed that HMA therapy in NP-AML produced a significantly superior OS compared to IC (19.1 vs. 9.6 mo, p=0.0165), whereas no significant OS difference was found in the P-AML patients (13.3 (HMA) vs. 10.3 mo (IC), p=0.3135). In the HMA cohort, OS was better in NP-AML compared to P-AML (19.1 mo vs. 13.2 mo, p=0.0276). Survival with LI treatment was inferior to IC or HMA in both P-AML and NP-AML cohorts (Figure 1C).The HMA treated cohort was then analyzed, based upon risk stratification using NCCN cytogenetic risk categories. Sample size was too small to assess OS in the favorable-risk patients (NP-AML, n=1; P-AML, n=1). In the intermediate risk patients (IRC), OS was similar between NP-AML and P-AML (23.97 months vs. 17.5 months, p=0.1650). In the poor-risk cytogenetics (PRC) subgroup, survival was superior in the NP-AML cohort compared to P-AML (11.58 months vs. 9.37 months, p=0.0132).Finally, outcome based upon the specific HMA administered (AZA vs. DEC) was compared (Figure 1B). AZA treatment was associated with a trend favoring improved OS in NP-AML compared to DEC (19.83 months vs. 11.13 months, p=0.2644). Moreover, AZA treatment statistically improved OS in NP-AML compared to P-AML (19.83 months vs. 14.43 months, p=0.0466). Survival outcomes with AZA vs DEC based on cytogenetic risk categories are illustrated in Figure 1B.ConclusionsHMAs represent effective frontline therapy for elderly patients with P-AML or NP-AML, with particular benefit compared to IC or LI in the NP-AML subset. In patients harboring poor-risk cytogenetics, HMA therapy produced an improvement in OS in NP-AMLvs.P-AML. [Display omitted] DisclosuresSallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Sweet:Incyte: Research Funding; Ariad: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Consultancy; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Lancet:Janssen: Consultancy; Erytech: Consultancy; BioSight: Consultancy; Bio-Path Holdings: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy.

The Danish Myelodysplastic Syndromes Database: Patient Characteristics and Validity of Data Records.

BackgroundThe Danish Myelodysplastic Syndromes Database (DMDSD) comprises nearly all patients diagnosed with myelodysplastic syndromes (MDS) in Denmark since 2010. The DMDSD has not yet been used for epidemiological research and the quality of registered variables remains to be investigated.ObjectiveTo describe characteristics of the patients registered in the DMDSD and to calculate predictive values and the proportion of missing values of registered data records.MethodsWe performed a nationwide cross-sectional validation study of recorded disease and treatment data on MDS patients during 2010–2019. Patient characteristics and the proportion of missing values were tabulated. A random sample of 12% was drawn to calculate predictive values with 95% confidence intervals (CIs) of 48 variables using information from medical records as a reference standard.ResultsOverall, 2284 patients were identified (median age: 76 years, men 62%). Of these, 10% had therapy-related MDS, and 6% had an antecedent hematological disease. Hemoglobin level was less than 6.2 mmol/L for 59% of patients. Within the first two years of treatment, 59% received transfusions, 35% received erythropoiesis-stimulating agents, and 15% were treated with a hypomethylating agent. For the majority of variables (around 80%), there were no missing data. A total of 260 medical records were available for validation. The positive predictive value of the MDS diagnosis was 92% (95% CI: 88–95). Predictive values ranged from 64% to 100% and exceeded 90% for 36 out of 48 variables. Stratification by year of diagnosis suggested that the positive predictive value of the MDS diagnosis improved from 88% before 2015 to 95% after.ConclusionIn this study, there was a high accuracy of recorded data and a low proportion of missing data. Thus, the DMDSD serves as a valuable data source for future epidemiological studies on MDS.

Characterization and Prognosis of Secondary Acute Myeloid Leukemia in an Asian Population: AML With Antecedent Hematological Disease Confers Worst Outcomes, Irrespective of Cytogenetic Risk.

Acute myeloid leukemia (AML) is a biologically heterogeneous disease that can be classified into de novo AML and secondary AML. Secondary AML can be further divided into therapy-related AML (t-AML) or AML evolving from antecedent hematological disorder (AHD-AML). This study evaluated the characteristics and prognosis of secondary AML in a homogeneous East Asian population who are often under-represented. This was a retrospective, longitudinal cohort study of Korean AML patients over 18 years old treated between January 2000 and December 2013. A total of 437 de novo AML (80.3%), 41 t-AML (7.5%), and 66 AHD-AML (12.1%) were evaluated. First, we found that secondary AML constituted about 19.7% of all AML cases, and t-AML was more prevalent than AHD-AML. Second, we determined AHD-AML as a prognostic factor for inferior survival, independent of other risk factors (HR=2.137, 95%CI=1.534-2.977, p<0.001). The induction response rates correlated well with the overall survival. Furthermore, AHD-AML was associated with worst treatment outcomes and prognosis regardless of cytogenetic risk or age. Interestingly, t-AML was generally associated with better outcomes compared to AHD-AML despite the similarities in treatment schema. Secondary AML represents a broad spectrum of diseases and t-AML should be addressed separately from AHD-AML.

Updated Results from the Venetoclax (Ven) in Combination with Idasanutlin (Idasa) Arm of a Phase 1b Trial in Elderly Patients (Pts) with Relapsed or Refractory (R/R) AML Ineligible for Cytotoxic Chemotherapy

Updated Results from the Venetoclax (Ven) in Combination with Idasanutlin (Idasa) Arm of a Phase 1b Trial in Elderly Patients (Pts) with Relapsed or Refractory (R/R) AML Ineligible for Cytotoxic Chemotherapy

Salvage Therapy Outcomes in a Historical Cohort of Patients with Relapsed or Refractory Acute Myeloid Leukemia

BackgroundPrognosis of patients with relapsed or refractory AML has been poor as no standard salvage therapy exists. Most trials of investigational agents begin in r/r AML and accrue a wide range of patients with different characteristics. Historical context for outcomes can be used as a reference for the development of future protocols and novel agents. The objective of this study was to evaluate outcomes of patients presenting with r/r AML in a single institution.MethodsWe analyzed the outcomes of patients who were treated for r/r AML for at least one treatment course at our institution between the years 2002 and 2016. At the time of inclusion in this study, patients had at least one prior treatment failure, were ≥18 years old at time of AML diagnosis, and had no central nervous system (CNS) involvement. Patients with acute promyelocytic leukemia were excluded.Descriptive characteristics of patients were summarized by proportions. Complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) rates were described as proportion with Wald 95% confidence intervals. Time to event analyses was estimated using the Kaplan-Meier method. Univariate and multivariate Cox models estimated p-values from Wald chi-square.ResultsA total of 1021 patients were included. Median age was 60 years (range, 18 - 87). At least one cytogenetic abnormality was present in 53.3% (n=546) of the population, 34.5% (n=352) had a history of an antecedent hematologic disease, and 10.5% (n=107) were therapy-related AML. For patients with available induction records, approximately 46% (295/635) were refractory. Among patients who achieved a CR after induction, 45% (118/264) had a CR duration <6 months.Overall, only a small proportion of all r/r AML patients achieved a CR2 and CR rates decreased with each subsequent salvage attempt (Table 1). Rates were lower among patients >60 years of age (1st salvage p=0.05, 2nd salvage p=0.003, 3rd salvage p=0.09). Among various types of salvage regimens, the range of CR was from 0 to 36%. Regimens based on high dose cytarabine (HDAC) were the most common (n=297). Although sample size was modest, HDAC regimens that additionally contained a FLT3 inhibitor induced the highest CR and CR/CRi rates (33% CR2, 44% CR3) (Table 2). Age (p=0.0006), cytogenetics (p<0.001), antecedent hematologic disease (p<0.001), duration of first remission (p<0.001), and year of relapse (p<0.001) were associated with CR in univariate analyses. In multivariate analyses, cytogenetics (p=0.004), antecedent hematologic disease (p<0.001), year of relapse (p=0.002), and platelet count (p=0.003) were associated with CR.Overall survival and event free survival were modest and decreased with subsequent salvage (Table 3). Age (p<0.001), cytogenetics (p<0.001), antecedent hematologic disease (p<0.001), de novo/therapy-induced AML (p=0.007), duration of first remission (p<0.001), and platelet count (p<0.001) were associated with survival in univariate analyses. In multivariate analyses, age (p<0.001), cytogenetics (p<0.001), antecedent hematologic disease (p<0.001), duration of first remission (p=0.002), platelet count (p=0.005) and blast count (p=0.014) were associated with survival.ConclusionOverall, most patients were unable to achieve a CR2+. Fewer patients were able to achieve subsequent CR after a second treatment failure or relapse. EFS was short due to most patients failing to achieve CR. Even at first salvage, OS was less than 1 year. These data demonstrate that patients with relapsed or refractory AML have poor overall outcomes and further emphasizes the need for additional options for these patients. These data can be used to help guide the development of novel therapeutic options in AML. [Display omitted] DisclosuresRavandi:Sunesis: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Kadia:Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy. DiNardo:Celgene: Honoraria; Abbvie: Honoraria; Bayer: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Karyopharm: Honoraria. Daver:Pfizer: Consultancy; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Pfizer: Research Funding; Kiromic: Research Funding; Sunesis: Research Funding; Karyopharm: Research Funding; ImmunoGen: Consultancy; BMS: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Sunesis: Consultancy; Alexion: Consultancy; Otsuka: Consultancy; Incyte: Research Funding. Short:Takeda Oncology: Consultancy. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Kim:Amgen: Employment, Equity Ownership. Kelsh:Amgen: Employment, Equity Ownership. Katz:Amgen: Other: Former employee and stockholder; Kite, a GILEAD Company: Consultancy. Yang:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen: Employment, Equity Ownership.

Potential Predictors of Induction Failure and Complete Remission Duration in FLT3-ITD Mutated Acute Myeloid Leukemia

Potential Predictors of Induction Failure and Complete Remission Duration in FLT3-ITD Mutated Acute Myeloid Leukemia

Safety, Efficacy, Pharmacokinetic (PK) and Biomarker Analyses of BCL2 Inhibitor Venetoclax (Ven) Plus MDM2 Inhibitor Idasanutlin (idasa) in Patients (pts) with Relapsed or Refractory (R/R) AML: A Phase Ib, Non-Randomized, Open-Label Study

Safety, Efficacy, Pharmacokinetic (PK) and Biomarker Analyses of BCL2 Inhibitor Venetoclax (Ven) Plus MDM2 Inhibitor Idasanutlin (idasa) in Patients (pts) with Relapsed or Refractory (R/R) AML: A Phase Ib, Non-Randomized, Open-Label Study

Hypomethylating Agents Versus Intensive Chemotherapy in Older Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

Abstract Background Acute myeloid leukemia (AML) is primarily a disease of older adults, with 40-50% of patients ≥ 70 years old at diagnosis. Optimal frontline therapy for elderly AML patients remains controversial. Intensive chemotherapy (IC) is often favored in those AML patients who present with leukocytosis (P-AML), yet the evidence to support this practice as opposed to lower intensity therapy is scarce. We aimed to investigate the outcomes of older patients with P-AML based on treatment choice of intensive chemotherapy (IC) vs hypomethylating agents (HMA). Methods We retrospectively analyzed 983 elderly AML patients (age ≥ 70 years) treated at Moffitt Cancer Center between 1995 and 2016. Patients with prior exposure to HMA for non-AML diagnoses were excluded. We focused on P-AML patients, defined as baseline WBC ≥ 10x109/L, who received initial therapy with either: intensive chemotherapy (IC) (defined as daunorubicin/cytarabine or equivalent) or hypomethylating agents (HMA) (azacitidine (AZA) or decitabine (DEC)). Age, type of AML, history of antecedent hematologic disease, cytogenetics (per European LeukemiaNet (ELN) criteria), Eastern Cooperative Oncology Group (ECOG) performance status, Charlson comorbidity Index (CCI), complete blood counts and myeloblast percentage at time of diagnosis were obtained for each patient. Kaplan-Meier analysis was performed to calculate overall survival (OS) and the log-rank test was used to determine significance where a p-value of 0.05 was defined as significant. Fisher's exact t-test, hazard ratios (HR) and confidence interval (CI) were calculated using GraphPad Prism v7.03. Univariate and multivariate analysis for the baseline characteristics and type of therapy were performed using SPSS v24.0 to determine prognostic impact. Results Within the entire cohort of older AML patients, we identified 156 who were treated with either HMA (n=41) or IC (n=115). Baseline characteristics of these patients are described in Figure 1A. Significant baseline differences in age, hemoglobin, WBC, ELN cytogenetic category, marrow blast %, and CCI score were observed between the HMA and IC groups. Most notably, the HMA group were older (median age 77 yrs vs 74 yrs, p=0.0037), had a higher incidence of poor-risk cytogenetics (36.6% vs 7%), and were more likely to have CCI score ≥ 3 (29.3% vs 8.7%). Median time of initial treatment was 4.3 months (range: 0.10-70.0 months) in the HMA group compared to 0.5 months (range: 0.33-1.90months) in the IC group. Median OS of the entire group was 7.85 mo. Median OS in the HMA-treated patients was superior to IC treated patients (13.7 mo vs. 5.1 mo, HR 0.63, 95% CI 0.443 - 0.886, p=0.0082) (Figure 1B). The 12 month survival rate was 55.0% in the HMA group and 31.0% in the IC group (p=0.0082). Fifty-two (33%) patients achieved CR/CRi. There was no difference in CR/CRi rates between HMA or IC treated cohorts (30.0% vs. 34.8%, p=0.6983). Rate of relapse upon achievement of CR/CRi was not statistically significant between HMA and IC cohort (41.7% vs. 62.5%, p=0.3181). The 30-day mortality rate was lower in the HMA group compared to the IC group (7.3% vs 24.4%, p=0.0217). Univariate analysis identified treatment type (p Conclusions Elderly patients (age ≥ 70) with proliferative AML appear to achieve a survival advantage with HMA-based frontline therapy compared to IC, despite a disproportionately higher incidence of traditionally adverse prognostic features (poor-risk cytogenetics, high CCI score) in the HMA group. The reasons for this observation are unclear, but could relate to a higher early death rate with IC or biologic/molecular features that induce greater sensitivity to HMAs, which should be studied in future analyses. Although this study was limited by small size and retrospective nature, our findings cast doubt on the notion that intensive therapy should be the standard frontline approach in elderly patients proliferative/high WBC AML. Download : Download high-res image (266KB) Download : Download full-size image Disclosures Sallman: Celgene: Research Funding. Padron: Incyte: Honoraria, Research Funding. Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Lancet: Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy; Pfizer: Other: Institutional research funding.

Phase 3, randomized, placebo-controlled trials evaluating glasdegib in combination with intensive or nonintensive chemotherapy in patients with untreated acute myeloid leukemia.

TPS7073 Background: Glasdegib is an oral Hedgehog pathway inhibitor with clinical activity in patients (pts) with untreated AML or higher-risk MDS, and improved survival when combined with low-dose cytarabine (AraC) in unfit pts with AML. BRIGHT AML1019 comprises two Phase 3, randomized (1:1), double-blind trials evaluating glasdegib 100 mg once daily (QD) or placebo (PBO) + chemotherapy in untreated adult AML (NCT03416179). The protocol includes 2 parallel, simultaneous trials: 1 with intensive chemotherapy (IC) and 1 with nonintensive chemotherapy (nIC). Methods: Both trials include pts aged ≥18 y with untreated AML (WHO 2016), including AML evolved from MDS or antecedent hematologic disease, or secondary AML. Key exclusions: inadequate organ function, acute promyelocytic leukemia, active CNS leukemia. Assignment to IC or nIC trial is per Investigator. In the IC trial, 400 pts are randomized (1:1) to glasdegib 100 mg QD or PBO on Day 1 and continue for up to 2 y or until post consolidation minimal residual disease (MRD)-negative status. Glasdegib or PBO are administered with 7+3 induction (AraC 100 mg/m2 IV for 7 days + daunorubicin 60 mg/m2 for 3 days); induction 2, if needed, will use 7+3 or 5+2. Consolidation consists of single-agent AraC 1 or 3 g/m2 IV over 3 h twice daily on Days 1, 3 and 5 every 28 days for ≤4 cycles; eligible patients may receive hematopoietic stem cell transplant. In the nIC trial, 320 pts are randomized (1:1) to glasdegib 100 mg QD or PBO, each with azacitidine 75 mg/m2 daily SC or IV for 7 days, in 28-day cycles. Treatments continue until disease progression, unacceptable toxicity, withdrawal or death. In both trials, glasdegib and PBO continue regardless of chemotherapy dose modifications/delays. The primary endpoint is overall survival. Secondary endpoints include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Clinical trial information: NCT03416179.

Acute Myeloid Leukemia: The Good, the Bad, and the Ugly.

Acute myeloid leukemia (AML) was initially subdivided according to morphology (the French-American-British system), which proved helpful in pathologic categorization. Subsequently, clinical and genomic factors were found to correlate with response to chemotherapy and with overall survival. These included a history of antecedent hematologic disease, a history of chemotherapy or radiation therapy, the presence of various recurrent cytogenetic abnormalities, and, more recently, the presence of specific point mutations. This article reviews the biology and responses of one AML subgroup with consistent response and good outcomes following chemotherapy (core-binding factor leukemia), and two subgroups with persistently bad, and even ugly, outcomes (secondary AML and TP53-mutated AML).

Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML

Preliminary Results from a Phase Ib Study Evaluating BCL-2 Inhibitor Venetoclax in Combination with MEK Inhibitor Cobimetinib or MDM2 Inhibitor Idasanutlin in Patients with Relapsed or Refractory (R/R) AML

Results of a Clinical Study of Pevonedistat (Pev), a First-in-Class NEDD8-Activating Enzyme (NAE) Inhibitor, Combined with Azacitidine (Aza) in Older Patients (Pts) with Acute Myeloid Leukemia (AML)

Results of a Clinical Study of Pevonedistat (Pev), a First-in-Class NEDD8-Activating Enzyme (NAE) Inhibitor, Combined with Azacitidine (Aza) in Older Patients (Pts) with Acute Myeloid Leukemia (AML)

Treatment-Related Morbidity and Mortality Associated with Remission Induction in Adolescent and Young Adult (AYA) Versus Young Adult Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Background:Acute myeloid leukemia is the most commonly diagnosed acute leukemia with a median age of diagnosis between 65 - 70 years; 45% of newly diagnosed AML patients are less than 65 years of age. Complete response (CR) rates following induction chemotherapy ranges between 60 - 80% in patients younger than 60 years old. However, limited data exists evaluating AML outcomes of adolescent and young adult (AYA), defined as 15 - 39 years, compared to adult patients less than 60 years old. Herein, we compare treatment-related outcomes of AYA versus adult AML patients.Methods:This was a single-center, retrospective study comparing treatment-related outcomes, morbidity and mortality between newly diagnosed AYA and adult AML patients receiving induction chemotherapy from July 1, 2009 to July 31, 2014 treated at Moffitt Cancer Center. Patients were excluded if less than 18 years of age, diagnoses of acute promyelocytic leukemia (APL) or myelodysplastic syndrome (MDS). The primary objective was to compare 30-day mortality between the AYA and adult AML patients admitted to MCC. Secondary objectives included 60-day mortality, death during induction, CR rates, overall survival (OS), receipt of hematopoietic stem-cell transplant (HSCT), infection, transfer to the intensive care unit (ICU), complications, organ failure, and chemotherapy toxicity.Results:A total of 176 patients were identified, of which 47 were aged 18 - 39 and 129 were aged 40 - 59. Baseline characteristics were similar among AYA and adult patients except for age, weight, body mass index, obesity, and those with greater than 3 comorbidities. Thirty-day mortality rates between AYA and adult patients were similar (2% vs 3%, p=0.596). Additionally, 60-day mortality (2% vs 6%), death during induction hospitalization (2% vs 5.5%), CR rates (70% vs 72%), receipt of HSCT (42.5% vs 47%), median OS (Not Reached vs 25.18 months, Figure 1), ICU transfer (10.5% vs 17%), time to infection (15.5 days vs 16 days), rate of infections (34% vs 33%), time to complication (8 days vs 10 days), rate of organ failure, and rate of chemotherapy toxicity were not significantly different between the two groups. Number of patients experiencing a treatment-related complication was significantly lower in AYA versus adult patients (74.5% vs 94%, p<0.05). Univariate analysis found AYA age group, receipt of HSCT, history of antecedent hematologic disease, and cytogenetic risk factor as significant variables impacting OS. A multivariate analysis identified cytogenetic risk factor (OR, 2.045; 95% CI 1.409 - 2.969), history of antecedent hematologic disease (OR, 1.635; 95% CI 1.018 - 2.628), and receipt of HSCT (OR, 0.397; 95% CI 0.254 - 0.62) as predictors for OS.Conclusion:Overall, there were no significant differences in treatment-related morbidity and mortality between AYA and adult newly diagnosed AML patients who received induction chemotherapy. Patients receiving HSCT, history of antecedent hematologic disease, and cytogenetic risk category showed an effect on multivariate analysis of OS while AYA age group was only significant in the univariate analysis. [Display omitted] [Display omitted] DisclosuresSweet:Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Survival Comparison Amongst Commonly Used Frontline Regimens in Patients Age 70 Years and Older with Acute Myeloid Leukemia (AML): A Single-Institution Study of Over 600 Patients

Abstract Introduction Treatment of elderly patients with acute myeloid leukemia (AML) is a therapeutic challenge. Elderly patients frequently have more biologically inherent resistant disease, along with comorbidities that together result in poor overall survival (OS). Optimal frontline therapy for elderly patients with AML remains controversial, and choice of regimen varies among clinicians. In this large, single-institution retrospective cohort study of AML patients over age 70, we present survival analysis and comparison amongst a variety of commonly used initial regimens. Methods 602 AML patients aged 70 or greater who received treatment between 1995 and 2014 in a single-large institution were retrospectively analyzed. Patients were categorized into 4 different treatment groups: High Intensity Therapy (defined as daunorubicin/cytarabine or equivalent), Hypomethylating Agent (HMA) Therapy, Low intensity Therapy (defined as low-dose cytarabine or similar without HMAs), and Supportive Care (including hydroxyurea if indicated). Age, type of AML, history of previous hematological disease, cytogenetics, ECOG performance status, comorbidities (Charlson Index), complete blood counts and blast percentage at time of diagnosis were obtained for each treatment category. Pairwise comparison of survival between different treatment groups was performed, using the stratified log-rank test and propensity score matching to adjust for potential treatment indication bias between groups. Within pairwise comparison groups, the stratified Cox proportional hazards regression model was used to assess correlation of the clinical variables with overall survival. Results Median age was 77 years (range 70 - 95) with a male predominance (M:F=68%:32%). ECOG Performance Status was 0 to 1 in 80% and 2 to 4 in 20% of patients. Per NCCN criteria, cytogenetics risk category was intermediate or favorable in 67% and unfavorable in 33%. Baseline median WBC, hemoglobin and platelet counts were 3.31 k/uL, 9.40 g/dL and 43 k/uL respectively. Median baseline bone marrow blast percentage was 35% (range 2% - 95%), and the large majority (445 of 550 patients - 81%) had peripheral blood blasts at the time of diagnosis. The majority of patients had secondary AML (61%) compared with de novo AML (39%). Of those with secondary AML, myelodysplastic syndrome (MDS) was the most common antecedent hematologic disease (97%), for which 36% had received prior HMAs. For frontline therapy, 238 (40%) patients received High Intensity Therapy; 110 (18%) received HMA Therapy, 67 (11%) received Low Intensity Therapy, and 187 (31%) received Supportive Care. Pairwise comparison between HMA Therapy and the 3 other treatment groups individually demonstrated statistically significant superior OS with HMA Therapy (median 13.3 mo; 95% CI 10.6 - 16.8 mo) compared to High Intensity Therapy (median 9.5 mo; 95% CI 7.4 - 10.9 mo), Low Intensity Therapy (median 5.9 mo; 95% CI 4.2 - 7.8 mo) and Supportive Care (median 2.5 mo; 95% CI 2.1 - 3.0 mo.). In addition, pairwise comparisons demonstrated superior OS with high vs low-intensity (p=0.0007), but no significant difference between Low-Intensity and Supportive Care (p=0.10). A pairwise comparison between HMA and High Intensity Therapy in the small subset of patients who had received prior HMA for MDS revealed extremely poor outcomes in both arms, with Conclusion In this analysis of a very large data set of patients over age 70 with AML, using pairwise comparison with propensity score matching, our results indicate a survival benefit with high intensity therapy or HMAs compared to supportive care or low-intensity (non-HMA) therapy. Interestingly, treatment with HMAs also resulted in better OS than traditional high intensity therapy. These data are contributing to an ongoing effort to design a comprehensive decision analysis model comparing treatment effectiveness according to baseline characteristics in AML patients 70 and older. Download : Download high-res image (128KB) Download : Download full-size image Figure 1 . Overall Survival Amongst Treatment Groups Disclosures Lancet: Kalo-Bios: Consultancy; Boehringer-Ingelheim: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy.