A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed N
                  ucleophosmin 1-mutated Acute Myeloid Leukemia

Abstract Background: Spleen tyrosine kinase (SYK) is a component of both lymphoid and myeloid cell signaling pathways and has been implicated in the pathogenesis of a subset of acute myeloid leukemia (AML) defined by dysregulated expression of the HOXA9 and MEIS1 transcription factors. Entospletinib (ENTO) is an oral, selective SYK inhibitor that is acceptably tolerated when administered with intensive induction and consolidation in newly diagnosed AML patients. In a phase 2 study, following induction with cytarabine and daunorubicin (7+3) plus ENTO, higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) were observed in patients with rearrangements of the KMT2A (MLL) gene (MLL-r) and mutations of the nucleophosmin 1 (NPM1) gene, both of which are associated with aberrant expression of HOXA9 and MEIS1, as compared to patients without these mutations. In an exploratory analysis, patients with HOXA9/MEIS1 expression levels above the median experienced superior overall survival (OS) as compared to patients with expression levels below the median. In the AGILITY trial, we hypothesize that the addition of ENTO to intensive induction/consolidation in newly diagnosed patients with NPM1-mutated AML will improve the rate of CR without evidence of measurable residual disease (MRD-negative CR) post-induction and duration of event-free survival (EFS). Methods: AGILITY will be a global, multi-center, double-blind, placebo-controlled trial of ENTO in combination with cytarabine plus daunorubicin or idarubicin induction (7+3) and age-adjusted high-dose cytarabine (HiDAC) consolidation in newly diagnosed AML patients aged 18-75 years who are candidates for intensive induction and harbor a documented NPM1 mutation based on local or central mutation testing. Patients with co-mutated FLT3 (internal tandem duplication or tyrosine kinase domain) and for whom midostaurin with 7+3 is indicated are excluded. Patients will be stratified based on age (<60 vs ≥60 years) and anthracycline administered during induction (daunorubicin vs idarubicin). Approximately 180 patients will be randomized to receive 7+3 induction and HiDAC consolidation with ENTO (400 mg orally twice daily) versus 7+3 induction and HiDAC with placebo. Patients with <5% leukemic blasts after 1 cycle of induction will proceed to the first cycle of HiDAC consolidation while patients with ≥5% residual blasts will undergo a second induction cycle. Patients who do not achieve CR after 2 cycles of chemotherapy (either 2 induction cycles or 1 induction and 1 consolidation cycle) plus ENTO or placebo will be designated as induction treatment failures (ITF). Patients who achieve or remain in CR after 2 chemotherapy cycles will be evaluated for MRD in bone marrow based on enumeration of mutant NPM1 alleles using a molecular assay. Patients may receive up to 3 cycles of consolidation with HiDAC and ENTO or placebo beyond chemotherapy cycle 2 per their original randomized treatment assignment. The number of consolidation cycles and timing of hematopoietic stem cell transplant (HSCT) or other post-consolidation therapy (if any) is at the discretion of the investigator. All patients will be followed for relapse and survival. The primary endpoint will be the rate of MRD-negative CR (<0.01% mutant NPM1 alleles). Patients without an evaluation of response and MRD after chemotherapy cycle 2 will be imputed as treatment failures for the analysis. A key secondary endpoint will be EFS, defined as time from randomization to the earliest occurrence of ITF, relapse from CR, or death from any cause. Patients without an event at the time of the EFS analysis will be censored at the last study evaluation they were event-free. EFS will be estimated using the Kaplan-Meier method and summarized by treatment group. Differences between treatment groups will be assessed with the log-rank test stratified by age (<60 vs ≥60 years) and choice of anthracycline in induction (daunorubicin vs idarubicin). OS will be analyzed in a similar manner. Key exploratory endpoints will be the correlation between recurring genomic mutations and response or progression and longitudinal assessment of peripheral blood for detection of NPM1-m alleles among patients who achieve MRD-negative CR post-induction. An independent data-monitoring committee will monitor emerging safety and efficacy data from this trial on an ongoing basis. Disclosures Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Minden: Astellas: Consultancy. Oellerich: Roche: Consultancy; Gilead: Research Funding; Kronos Bio, Inc.: Consultancy; Merck KGaA: Consultancy, Research Funding. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Syndax Pharmaceuticals: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy. Elder: PharPoint Research, Inc.: Current Employment. Kumar: Kronos Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Bray: Kronos Bio, Inc.: Consultancy. DiMartino: Kronos Bio, Inc.: Current Employment, Current equity holder in publicly-traded company. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. OffLabel Disclosure: Entospletinib is an investigational therapy

Download Full-text

Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

Download Full-text

Preliminary Results from a Phase 1 Study of APVO436, a Novel Anti-CD123 x Anti-CD3 Bispecific Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2020-141619 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Justin M. Watts ◽

Tara Lin ◽

Eunice S. Wang ◽

Alice S. Mims ◽

Elizabeth H. Cull ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 1 ◽

Cytokine Release ◽

Publicly Traded ◽

Advisory Committees ◽

Acute Myeloid

Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with > 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy > 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT < 1.5 x ULN and alanine aminotransferase < 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.

Download Full-text

Clinical Characteristics and Outcome in IDH1/2 Mutant AML Patients - Analysis of 3898 Newly Diagnosed Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-118128 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1461-1461 ◽

Cited By ~ 2

Author(s):

Jan Moritz Middeke ◽

Christoph Rollig ◽

Michael Kramer ◽

Alwin Kramer ◽

Tilman Bochtler ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Normal Karyotype ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Acute Myeloid

Abstract Purpose Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are one of the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Several IDH inhibitors are currently in late stage clinical development with Enasidenib, an IDH2 inhibitor, being recently approved by the FDA. Previous analyses have reported differential impact on response to chemotherapy and outcome, depending on the IDH-mutation type, co-occurring mutations and cytogenetic abnormalities, as well as the variant allele frequency (VAF) of IDH mutations. In order to better understand its prognostic role, we analyzed newly diagnosed AML patients enrolled in prospective trials of the Study Alliance Leukemia (SAL) to investigate the impact of IDH1/2 mutations on outcome. Patients and Methods All AML patients consecutively enrolled into intensive AML treatment protocols of the SAL or into the SAL registry were included in this analysis. Next-generation sequencing (NGS) on an Illumina MiSeq-system was performed to detect IDH1/2 mutations using pre-treatment samples. Overall survival (OS) and response to therapy were analyzed for all patients with intensive treatment and according to the mutational status. Results Overall, samples of 3898 patients were analyzed. The median follow-up was 91 months (95% CI 87.2 - 93.9). Patients' characteristics are shown in Tbl.1. Three-hundred twenty-nine patients (8.4%) had IDH1 mutations and 423 (11%) had IDH2 mutations; both mutations were found in 12 pts, so the overall mutation rate in IDH1 and 2 was 19% (740/3898 patients). Of the IDH1 variants, the most common ones were the R132C found in 143 patients (43%) and R132H in 137 patients (42%). For IDH2, 324 patients had the R140Q (77%) and 80 patients the R172K (19%) variant. According to the two main variants of the more common IDH2 mutations, as reported before, the IDH2 R172K was mutually exclusive with NPM1 and/or FLT3-ITD mutations. Overall, there was a trend for increased OS for patients with IDH2 R172K (26 vs. 15 months) as compared to those with R140Q. Considering only patients with a normal karyotype and no NPM1/FLT3-ITD mutation, these patients (n=27) had a highly significant better OS than patients with IDH2 R140Q (46.3 vs. 13.1 months, p=.012), supporting the findings published by Papaemmanuil et al. (NEJM 2016). In IDH1-mutated patients, we observed statistically significant differences in baseline characteristics between the two most common mutation types, IDH1 R132C and R132H. Patients carrying the R132C mutation were older (62 vs. 55 years, p=.001), had lower WBC (3.6 vs. 21 Gpt/L, p≤.001) and were less likely to have a normal karyotype (43% vs. 66%, p=.002), NPM1 (23% vs. 66%, p=<.001), and FLT3-ITD mutations (8% vs. 27%, p<.001) than those with the R132H variant. In univariate testing, the CR rate was also statistically significant lower in patients with IDH1 R132C (53% vs. 72%, p≤.001), with a median OS of 12.9 months compared to 17.4 months for patients with R132H variant (p=.08). In multivariate analysis including age, WBC, NPM1 and FLT3 status, and ELN risk, the CR rate was significantly lower in patients with the IDH1 R132C variant (p=.038). The median IDH VAF was 38% (range, 0.1 - 58) with no difference according to the different types of mutation. Patients with a VAF > 30% had a significantly higher BM blast count (73% vs 40% for VAF≤5%) and WBC (21.2 Gpt/L vs. 3.7 Gpt/L) at baseline, but there was no clear impact on CR rate or OS found in multivariate analysis. Conclusion In this large cohort of AML patients with IDH1/2 mutations, we found significant and so far not reported differences for one of the two most prominent mutations types of IDH1. The R132C variant was associated with increased age, lower WBC, and lower NPM1 and/or FLT3 co-mutation rate. Further, these patients had lower CR rates and a trend for shorter OS. For IDH2 we were able to reproduce findings on co-mutations and showed a favorable outcome for intensively treated patients with a normal karyotype and no NPM1/FLT3-ITD mutation and the IDH2 R172K variant, providing additional evidence for classification as a separate AML entity. Disclosures Middeke: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Scholl:Alexion: Other: Travel support; Abbivie: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; MDS: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Brümmendorf:Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Novartis: Consultancy, Research Funding. Burchert:Novartis: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Johnson & Johnson: Research Funding; Roche: Research Funding; Eisai: Research Funding; Affimed: Research Funding; Novartis: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Schetelig:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau.

Download Full-text

Prevalence of Inherited Predisposition Syndromes in Young Patients with Acute Myeloid Leukemia and Aberrant Karyotype

Blood ◽

10.1182/blood-2020-142815 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Martin Kirschner ◽

Benjamin Rolles ◽

Martina Crysandt ◽

Christoph Röllig ◽

Friedrich Stolzel ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chromosome 8 ◽

Hek293 Cells ◽

Newly Diagnosed ◽

Inclusion Criteria ◽

Advisory Committees ◽

Acute Myeloid

Introduction Recent studies indicate that particularly in a subgroup of younger patients, acute myeloid leukemia (AML) develops due to an inherited genetic predisposition linked to mutations in genes such as ANKRD26, SAMD9, SAMD9-L, GATA-2, genes causing telomere biology disorders or Shwachman-Diamond syndrome. However, the prevalence of so-called "AML predisposition syndromes" (APS) underlying newly diagnosed cases with AML is unknown. Actual screening strategies for APS are based on the family history and clinical/genetic features. There is growing evidence that APS frequently manifest themselves with an oligosymptomatic phenotype or are lacking specific symptoms altogether. Furthermore, molecular analysis of the clonal population without additional analysis of non-clonal cells do not allow the discrimination between inherited and acquired changes. Thus, new approaches to identify the subset of patients with underlying APS in adult newly diagnosed AML patients are needed. One frequent feature observed in APS is younger age at the time of diagnosis and the initial presence of an aberrant karyotype. Along this line, we retrospectively screened the German SAL-AML registry using age and the presence of an aberrant karyotype as pre-defining parameters to analyze the prevalence of APS in this selected cohort. Patients and methods The database of the German SAL-AML registry includes over 5207 patients with AML. We screened for patients below 35 years of age and with any type of numerical or structural chromosomal aberration at first diagnosis. DNA samples of patients achieving cytological remission (CR) and available samples of peripheral blood or bone marrow were selected. CR samples were chosen to reduce potential contamination by malignant AML blasts. Patients were screened for pathogenic variants using a self-designed NGS panel containing the entire coding sequences of ACD, ANKRD26, CTC1, DDX41, DKC1, ERCC6, ETV6, GATA1, GATA2, LIG4, NHP2, NOP10, PARN, POT1, RPA1, RPL11, RPL15, RPL26, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS7, RTEL1, SAMD9, SAMD9L, SBDS, SRP72, TERC, TERF1, TERF2, TERT, TINF2, TPP1 and WRAP53. An inherited variant was considered in all patients with a variant allele frequency between 40-60% for heterozygous variants and >90% for homozygous ones. To analyze the functional consequence of SAMD9 variants, proliferation assays with HEK293 cells transfected with the respective identified variant was carried out. Results and discussion On the basis of the inclusion criteria mentioned above, we were able to identify 41 patients. All cases except one were considered de novo AML by the treating physicians and received an anthracycline/cytarabine based induction chemotherapy. Mean age of the 41 patients was 26 ± 5 years (mean ± S.D.). Predominant karyotypic aberration were abnormalities of chromosome 8 (18/41) as well as a complex aberrant karyotype (29/41). NGS analysis revealed five different heterozygous mutations in approx. 10% (4/41) of patients: GATA2 c.1009C>T p.(Arg337Ter), SBDS c.183_184delInsCT and c.258+2T>C (both mutations in the same patient), TINF2 c.848C>A p.(Pro283His), SAMD9 c.2854G>C p.(Gly952Arg). The variants in GATA2, SBDS and TINF2 are known to be pathogenic. For SAMD9, in vitro experiments showed increased inhibition of cell growth compared to wild-type supporting the pathogenicity of the mutation. Focusing on the clinical outcome, 50% (2/4) of the identified APS patients received allogeneic transplantation during follow-up compared to 65% (24/37) in the group without detectable mutations. Median survival in the APS group was significantly shorter with 3.2 months compared to 105.3 months in the remaining 37 AML patients (p<0.001). Conclusions Using age and karyotype as selection criteria, we were able to identify an inherited APS in 10% of newly diagnosed AML patients below 35 years with chromosomal aberrations reaching CR. Obviously, our study is limited by rather stringent inclusion criteria not allowing overall conclusions on the incidence of APS in newly diagnosed AML. However, age and karyotype might provide simple clinical parameters to trigger genetic screening for inherited APS in addition to the actual recommendations. Given the significant difference in survival in patients with and without underlying APS, our study clearly supports inclusion of screening for APS in this cohort pending prospective validation. Figure Disclosures Röllig: Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; Janssen-Cilag GmbH: Speakers Bureau; BiolineRx: Research Funding. Panse:Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy. Jost:Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: travel support; JAZZ: Other: travel support.

Download Full-text

Associating Ex Vivo Drug Sensitivity with Differentiation Status Identifies Effective Drug Combinations for Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-152043 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1301-1301

Author(s):

Christopher A. Eide ◽

Stephen E. Kurtz ◽

Andy Kaempf ◽

Nicola Long ◽

Daniel Bottomly ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Drug Sensitivity ◽

Ex Vivo ◽

Single Agent ◽

Publicly Traded ◽

Advisory Committees ◽

Acute Myeloid

Abstract The development of molecularly-targeted therapies to improve outcomes relative to chemotherapy for acute myeloid leukemia (AML) is impeded by the heterogeneity of genetic aberrations that contribute to disease. Among the multitude of biological mechanisms that lead to AML disease initiation and progression is dysregulation of cytokine signaling pathways, a hallmark of chronic inflammation, which contribute to the growth, survival, and differentiation state of AML cells. We have previously shown that IL-1β, a pro-inflammatory cytokine expressed by many cell types including macrophages and monocytes, stimulates proliferation of leukemic blasts independent of mutational status in primary AML samples via enhanced phosphorylation of p38α MAPK, an effect that can be blocked by IL-1 receptor knockdown or by pharmacologic inhibition (Carey 2017). Additionally, recent studies have shown sensitivity to the approved BCL2 inhibitor venetoclax in AML associates with undifferentiated leukemic cells (Pei 2020; Zhang 2018; Majumder 2020). Based on these associations, we evaluated the combination of doramapimod (DORA), a p38 MAPK inhibitor, with venetoclax (VEN) for potential enhanced sensitivity on primary AML cells. Ex vivo drug screening of primary AML patient samples (n=335) revealed significantly enhanced efficacy of VEN+DORA compared to either single agent (Nemenyi test; p<0.0001). This broad sensitivity of the VEN+DORA combination was not significantly associated with an array of clinical, genetic, and mutational features in the patient samples tested, in contrast to single agents, particularly VEN. Analysis of blood cell differential counts of patient samples tested identified increased monocyte levels were significantly correlated with sensitivity to DORA and resistance to VEN as single agents (Spearman r = -0.3 and 0.6; p<0.0001), associations that were not apparent with the combination. For patient samples with accompanying FAB differentiation state-based designations (n=108), sensitivities of the combination were similar across classifications of undifferentiated (M0/M1) through monocytic (M4/M5) acute leukemia. In contrast, single-agent VEN was significantly more sensitive in undifferentiated compared to monocytic specimens, whereas DORA sensitivity showed the reverse trend (though to a lesser degree). These differences in sensitivity were further validated by immunophenotyping data where available (n=105), which showed surface markers associated with resistance to VEN (CD11b, CD14, CD16, CD56, CD64, HLADR; Wilcoxon Rank Sum, p<0.001 to p=0.007) or sensitivity to VEN (CD117; p=0.001) or DORA (CD14; HLADR; p=0.004). By contrast, none of these associations significantly distinguished sensitivity for the VEN+DORA combination. Expression levels of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were concordant with their respective drug sensitivities associated with FAB classification; that is, significantly higher levels of BCL2 in M0/M1 leukemias and MAPK14 in M4/M5 cases (Mann-Whitney test; p<0.0001; n=145). Further dissection of transcriptomic and drug sensitivity data revealed strong correlation and gene set enrichment for DORA and VEN sensitivities with monocyte-like and progenitor-like signatures, respectively (n=225), for cell differentiation states previously described for AML (van Galen 2019), and these associations diminished for the combination treatment. Lastly, the VEN+DORA combination enhanced efficacy and synergistic inhibition was confirmed using human AML cell line models tested with a matrix of potential dose concentrations. Taken together, these findings suggest that exploiting distinct, complementary sensitivity profiles of targeted therapies with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers an opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML. Disclosures Druker: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Recludix Pharma, Inc.: Consultancy; EnLiven: Consultancy, Research Funding; Pfizer: Research Funding; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Merck & Co: Patents & Royalties; Aileron: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Nemucore Medical Innovations, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Tyner: Genentech: Research Funding; Takeda: Research Funding; Astrazeneca: Research Funding; Constellation: Research Funding; Agios: Research Funding; Petra: Research Funding; Incyte: Research Funding; Array: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Schrodinger: Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood-2020-140584 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Geoffrey Fell ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Remission Rate ◽

Conventional Chemotherapy ◽

Advisory Committees ◽

Secondary Aml ◽

Grade 3 ◽

Acute Myeloid

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

Download Full-text

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

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

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

Download Full-text

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

Blood ◽

10.1182/blood.v128.22.338.338 ◽

2016 ◽

Vol 128 (22) ◽

pp. 338-338

Author(s):

Bradstock Kenneth ◽

Emma Link ◽

Juliana Di Iulio ◽

Jeff Szer ◽

Paula Marlton ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Consolidation Therapy ◽

Advisory Committees ◽

Free Survival ◽

Acute Myeloid

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

Download Full-text

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

Blood ◽

10.1182/blood.v122.21.3402.3402 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3402-3402

Author(s):

Seung-Ah Yahng ◽

Jae-Ho Yoon ◽

Sung-Eun Lee ◽

Seung-Hwan Shin ◽

Byung-Sik Cho ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Research Funding ◽

De Novo ◽

Remission Induction ◽

Advisory Committees ◽

Induction Regimen ◽

Acute Myeloid

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

Download Full-text

Outcomes By Best Response with Hypomethylating Agent Plus Venetoclax in Adults with Previously Untreated Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-149782 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2292-2292

Author(s):

Virginia Olivia Volpe ◽

Akriti G Jain ◽

Onyee Chan ◽

Eric Padron ◽

David A. Sallman ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Free State ◽

Advisory Committees ◽

Best Response ◽

Baseline Characteristics ◽

Acute Myeloid

Abstract Background: Venetoclax plus hypomethylating agents (HMA) (HMA+VEN) is a standard of care treatment for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. In the phase 3 VIALE-A trial, azacididine (aza)+VEN compared to aza alone demonstrated an improved overall survival of 14.7 months versus 9.6 months, respectively. A common toxicity with HMA+VEN is myelosuppression. The prognostic implications of incomplete count recovery despite leukemia free state after HMA+VEN treatment in AML is unclear. We aimed to compare the outcomes of those who achieved complete remission (CR), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) in AML patients treated frontline with HMA+VEN. Methods: Patients seen at Moffitt Cancer Center between 2019 and 2021 diagnosed with AML and treated with frontline HMA+VEN were retrospectively evaluated and included for analysis. Patients were stratified by best response; either CR, CRi, or MLFS. Baseline characteristics were compared by chi square (categorical variables) and t- test (continuous variables). Survival estimates were calculated using the Kaplan-Meier method from date of diagnosis and groups were compared using log-rank test. Results: Of the 102 patients treated with HMA+VEN in the frontline setting, 48% (n=49) had blast clearance with a best response of CR in 27/102 (26.4%), CRi in 16/102 (15.7%), or MLFS in 6/102 (5.9%). The remainder had residual disease. Baseline characteristics were similar among the three response groups (Table 1) as was mutational distribution (Table 2). There was no difference between AML WHO classification subtype (p= .148). Decitabine or aza was used at the discretion of the treating physician did not significantly impact responses (p= .225). In those who achieved CR, 14% had prior therapy related AML compared to 37.5% in CRi and 33.3% in MLFS (p= .314). Antecedent MDS or MPN with transformation to AML was seen in 22.2%, 18.8%, and 66.7% of CR, CRi, and MLFS respectively (p= .029). Of those, 3.7% in CR group had HMA use for prior MDS/MPN compared to 0% in CRi and 50% in MLFS (p= .000). The median relapse free survival was not reached for CR, CRi, and MLFS (Figure 1), it is important to note that 3 of the 6 MLFS patients died without relapse . At median follow up of 23 months, median overall survival (OS) in the CR group was significantly longer, 31 months, compared to 18 months in the CRi group and 8.5 months in the MLFS group (p=0.0415) (Figure 2). Transplant was achieved in 26% of CR and 6.3% of CRi and 0% of MLFS and was not significant among the groups (p = .124). Conclusion: Patients who received frontline HMA+VEN for AML directed therapy and achieved CR/CRi had better survival compared to those who achieved MLFS. Our data suggest that incomplete recovery of blood counts plays a significant role in overall survival regardless of leukemia free state. Further, the data demonstrate significantly higher secondary AML with antecedent MDS or MPN in the MLFS group compared to CR and CRi groups. Of those, prior HMA therapy was also identified as significantly higher in the MLFS group compared to CR and CRi groups which may contribute to the prolonged cytopenias and worse OS. While the limitation to this study is overall small number of patients, it suggests that a goal of CR over CRi or MLFS is desirable for superior OS. In the future, it would be of interest to incorporate the rates of responses and variables that may have an impact such as therapy dose adjustment, time to response, and delays in therapy due to cytopenia. Additional studies identifying dose adjustments or other ways to improve hematologic recovery would be valuable to potentially improve outcomes in this difficult to treat population. Figure 1 Figure 1. Disclosures Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Kura: Research Funding. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy. Sweet: AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text