scholarly journals Combination Treatment of Venetoclax and Hypomethylating Agents (HMA) or Low-Dose Cytarabine (LDAC) for Patients with Acute Myeloid Leukemia (AML) - Real-World Data from Two German Academic Centers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1257-1257
Author(s):  
Laura K. Schmalbrock ◽  
Krischan Braitsch ◽  
Paul Jung ◽  
Irmgard Bumeder ◽  
Philipp Kiewe ◽  
...  
Keyword(s):  
Combination Treatment ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Treatment Cycle ◽  
Risk Group ◽  
Previous Treatment ◽  
Advisory Board ◽  
First Line ◽  
Low Dose Cytarabine

Abstract Introduction Treatment with the BCL-2 inhibitor Venetoclax (VEN) in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) has shown encouraging results in patients with acute myeloid leukemia (AML). In contrast to the FDA, EMA approval for unfit AML patients was given only recently, and VEN combinations have therefore often been used as off-label treatment for relapsed/refractory (r/r) AML patients. We conducted a retrospective study of 73 unfit or r/r AML patients treated with a VEN combination between 2017 and 2021 at two German university hospitals. Methods Data was collected by medical chart review and included genetics, ELN2017 risk classification, previous treatment lines, courses of VEN treatment as well as outcome. All statistical tests were performed with GraphPad Prism. The median time of follow-up was 8.3 months. Results At beginning of VEN treatment, the median age was 73 (20-85) years (Table 1). The majority of patients had a secondary (s) AML [n=34 (47%)] and was assigned to the adverse ELN2017 risk group [n=32 (44%)]. Mutations in isocitrate-dehydrogenase 1/2 genes (IDH1/2) were the most frequent alteration [n=19 (26%)]. Before VEN treatment, a total of n=58 (79%) patients had received prior treatment including intensive chemotherapy [n=36 (49%)] and allogeneic stem cell transplantation (allo-HSCT) [n=26 (36%)]. Twenty-five (34%) patients were treated with >4 cycles HMA or LDAC before VEN initiation. VEN was given as first-line treatment in n=15 (21%) patients and started during the first or second treatment cycle of HMA/LDAC. The initial VEN dosage after ramp-up during cycle 1 was in median 400mg (50-800mg). Patients received VEN in combination with azacytidine [n=34 (47%)], decitabine [n=18 (25%)] or LDAC [n=20 (28%)]. In median, patients had received 3 (1-17) VEN cycles at data cut-off. VEN was initiated after progression on HMA/LDAC treatment (>2 cycles) in n=35 (48%) patients. In most patients VEN was discontinued or dose-adjusted during treatment [cycle 1 n=37 (51%), after cycle 1 n=43 (59%)]. Response assessment was available for n=58 (79%) patients, of which n=18 (25%) achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi), n=24 (33%) a partial remission (PR) or stable disease (SD), and n=16 (22%) were refractory to VEN combination treatment. The overall response rate (ORR) including CR/CRi/PR patients was 47% and not influenced by age or previous treatments including allo-HSCT and HMA pretreatment. Achievement of CR/CRi was significantly better in patients with IDH1/2 and/or NPM1 mutations (Figure 1). The median overall survival (OS) of the entire cohort was 6.5 months. OS was significantly better in patients achieving a CR/CRi (20.3 months) as compared to patients with PR/SD/RD. (p<0.0001; Figure 2 A). OS was shorter in patients with more than two prior treatment lines (p=0.01, Figure 2 B) and in patients who had received allo-HSCT (p=0.05, Figure 2 C). There was no significant impact on OS with respect to age (>=65 years), ELN2017 risk group or previous HMA treatment. OS was however significantly longer in patients harboring NPM1 and/or IDH1/2 mutations (p=0.016; Figure 2 D). Conclusions Our real-world analysis demonstrates that VEN combination treatment is feasible and effective also in r/r AML patients. Response rates and survival were lower than in patients treated with VEN combinations in first line (DiNardo, NEJM 2020) and in our cohort highly influenced by the number of previous treatment lines. As in patients treated with VEN combinations at fist line, the NPM1 and IDH1/2 genotype was associated with better response and survival. Further studies with larger cohorts are needed to investigate the role of VEN combinations in r/r AML. Figure 1 Figure 1. Disclosures Westermann: Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Novartis: Consultancy, Honoraria; BMS: Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Stem Cell Line: Consultancy, Honoraria. Bullinger: Seattle Genetics: Honoraria; Bayer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Honoraria; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Hexal: Consultancy. Keller: Abbvie: Other: Advisory Role. Krönke: BMS/Celgene: Other: Advisory board; Abbvie: Other: Advisory board. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. OffLabel Disclosure: Venetoclax was used "off-lable" in unfit and relapsed/refractory AML patients in combination with HMA/LDAC.

scholarly journals Budget Impact of Glasdegib in Combination with Low-Dose Cytarabine for the Treatment of First-Line Acute Myeloid Leukemia in the United States

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5852-5852
Author(s):  
Ha Anh Pham ◽  
Sandra Milev ◽  
Shujun Li ◽  
Denise Zou ◽  
Yannan Hu ◽  
...  
Keyword(s):  
Incremental Cost ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Budget Impact ◽  
Treatment Options ◽  
Eligible Patient ◽  
Base Case ◽  
First Line ◽  
Low Dose Cytarabine

I ntroduction Acute myeloid leukemia (AML) is an orphan disease and has one of the lowest five-year survival rates among myeloid malignancies in United States (US) adults (28.3% on average, 5% of which are aged 65 years or older). Older patients with AML have few treatment options and are often not candidates for intensive induction chemotherapy, therefore novel therapeutic strategies are needed. A phase II randomized study (Cortes et al. 2019) among newly diagnosed AML patients who were not candidates for intensive induction chemotherapy demonstrated improved overall survival (OS) in patients treated with glasdegib in combination with low-dose cytarabine (LDAC) compared to patients receiving LDAC alone. The present analysis estimated the budget impact of including glasdegib combined with LDAC as first-line treatment for these AML patients from a US health plan perspective. Methods The budget impact was assessed using a decision analytic model that compared the current market environment where glasdegib + LDAC was not included with a new market environment where glasdegib + LDAC was included. The comparators in the model were LDAC alone, azacitidine, decitabine, and venetoclax combined with LDAC, azacitidine or decitabine. The budget impact was calculated based on epidemiology inputs, market share inputs, clinical inputs and all relevant cost inputs (i.e. drug and administration cost, medical resource use cost, adverse event cost). The base case was calculated for a US commercial health plan of 1 million members with a time horizon of 3 years. The main outcomes were total costs of current and new market environments, incremental budget impact, incremental cost per member per month (PMPM) and incremental cost per treated patient per month (PTPPM). Both deterministic sensitivity analyses and scenario analyses were performed to assess the uncertainty of the structure and inputs of the model. Results The analysis estimated an eligible patient population of 19 AML patients per year (per million members) who are not candidates for intensive induction chemotherapy. Of these: 2, 4 and 6 patients were estimated to receive glasdegib + LDAC in years 1, 2 and 3, respectively. In the base case, the incremental budget impact of glasdegib + LDAC was $179,290 in year 1, $262,694 in year 2 and $346,098 in year 3. This translated into an incremental cost PMPM of $0.0149, $0.0219, and $0.0288 in years 1, 2, and 3, respectively. The model results were most sensitive to the mean OS of glasdegib + LDAC. Conclusions The introduction of glasdegib + LDAC as a treatment for newly diagnosed AML patients who are not candidates for intensive induction chemotherapy has a small impact on the budget of US payers, given the small size of the eligible patient population. The model results suggest glasdegib + LDAC provides an alternative treatment option while extending life at minimal incremental cost for health plans. As such, glasdegib + LDAC may provide substantial value for money spent on treatment of these AML patients in the US for which treatment options are few. Disclosures Pham: Pfizer: Consultancy, Other: funding from Pfizer. Milev:Evidera: Consultancy, Other: funding from Pfizer. Li:Evidera: Consultancy, Other: funding from Pfizer. Zou:Evidera: Consultancy, Other: funding from Pfizer. Hu:Ingress-health: Consultancy, Employment, Other: funding from Pfizer. Heeg:Ingress-Health: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership.

scholarly journals Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 458-458 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Alessandra Iurlo ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Advisory Board ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: 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, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

scholarly journals Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 890-890
Author(s):  
Andrew Wei ◽  
Stephen A. Strickland ◽  
Gail J. Roboz ◽  
Jing-Zhou Hou ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Naïve ◽  
Equity Ownership ◽  
Low Dose Cytarabine

Abstract Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of &gt;60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, &lt;1 to 21 months). Thirty-eight (62%) of these patients achieved CR/CRi with a median duration of CR/CRi of 14.9 months (95% CI, 5.6 months to not reached [NR]; Figure). Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months); the observed 12-month OS was 46% (95% CI, 33-58%). Only 1 patient has subsequently undergone bone marrow transplantation. Treatment-emergent grade 3/4 AEs (in ≥20% of 61 patients) were thrombocytopenia (59%), neutropenia (46%), febrile neutropenia (36%), anemia (28%), and decreased WBC count (26%). One case (2%) of tumor lysis syndrome occurred. Serious AEs (in ≥3 of 61 patients) were febrile neutropenia (20%), malignant neoplasm progression (13%), lung infection/pneumonia (13%), and sepsis (7%). The 30-day mortality rate was 3%; causes of death were disease progression (n=1) and lung infection (n=1). Common recurrent mutations in 53 patients who received VEN 600 mg are shown in the Table. All patients with an NPM1 mutation (including 3 with a co-mutation in FLT3-ITD) achieved CR/CRi. Patients with DNMT3A, FLT3-ITD, and SRSF2 mutations had CR/CRi rates of ≥75%, whereas those with TP53 mutations had the lowest CR/CRi rates of 44%. For patients with CR/CRi, median OS was 18.4 months (95% CI, 13.5 months to NR). The 12-month OS rate for patients in the 600-mg VEN cohort who achieved CR/CRi was 70.4% from Kaplan-Meier estimates, with 11 deaths. Among 19 patients who received study treatment ≥12 months, 17 remain alive. The longest, ongoing, disease-free follow-up after treatment completion is 12 months. Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Figure Figure. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

scholarly journals Progressive Hyperleukocytosis during Initial Therapy Is a Predictive Marker for Differentiation Syndrome and Early Mortality in Adult Patients with Acute Promyelocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4009-4009
Author(s):  
Jae-Ho Yoon ◽  
Heeje Kim ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Risk Group ◽  
Early Death ◽  
Initial Therapy ◽  
High Risk Group ◽  
Advisory Committees ◽  
Leukocyte Counts ◽  
Low Dose Cytarabine

Abstract Background: Acute promyelocytic leukemia (APL) is classified into a favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is lower than another acute myeloid leukemia (AML) subtypes, but we confront higher incidence of early deaths caused by fatal complications including bleeding events and differentiation syndromes (DS) during initial therapy. Recently, although arsenic trioxide (ATO) is introduced with a better survival outcome, the results were from data of low to intermediate-risk group. Thus, patients in high-risk group still show poor survival outcome with high probability of early complications and deaths. We calculated the incidence of DS and early deaths, and tried to find out affecting factors for those early events. Methods: In this single center retrospective study, 259 APL patients (median 42 years old (16-72), follow-up was 65.4 months (11.1 - 170.5) from 2002 to 2014 were analyzed. APL was diagnosed by RT-PCR method for detection of PML-RARa and all patients were available with cytogenetic results. All except 5 patients with normal karyotype was identified with t(15;17)(q22;q21) and 77 showed combination of additional karyotypes. All patients were supported with sufficient transfusion and received ATRA. Our treatment protocol was based on the modified AIDA protocol using ATRA and idarubicin monotherapy (Sanz et al. Blood. 1999; 94: 3015-21) but some patients with comorbidity were treated with ATO, low-dose cytarabine, and ATRA alone for remission induction. For hyperleukocytosis, we conducted leukapheresis when leukocyte counts exceeded 50 (x109/L) and some were treated with hydroxyurea, cytarabine and prophylactic dexamethasone. High-risk group was determined according to the Sanz criteria which presented leukocyte count > 10 (x109/L) at diagnosis. For leukocyte count, we checked diagnostic level (WBCdx) and the maximal level (WBCmax) during initial therapy and identified a group which showed a meaningful increment of WBCmax compared to WBCdx. Results: ATRA was applied in 258 patients and 217 (84.1%) were treated with idarubicin, 13 (5.0%) were with ATO, 3 (1.2%) were with low-dose cytarabine. Eight-week cumulative incidence of early death and DS was 13.5% and 17.8%, and hematological CR was identified in 222 (86.0%) patients. Five-year OS and EFS was 76.8% and 69.8%, and CIR rate was 15.7%. Six patients showed clonal evolution to therapy-related AML and 3 patients died in CR. FLT3-TKD and FLT3-ITD mutation was identified in 12 (7.3%) and 34 (20.7%) patients, and PML-RARa BCR3 and BCR1 subtype was identified in 70 (36.8%) and 120 (63.2%) patients, respectively. For leukocyte counts, except for WBCdx higher than 43 (x109/L), which showed significantly higher rate of early death and DS, patient groups with WBCdx <10 (x109/L) vs. 10 to 43 (x109/L) showed no differences regarding early death or DS. We identified that the significance of WBCdx has been changed with increment during initial therapy which revealed WBCmax was more influential. Among the patients with WBCdx <43 (x109/L), WBCmax increased higher than 43 (x109/L) was related with higher incidence of early death (35.5%) and DS (30.6%), while more DS (40%) was identified in patients with higher increment ratio from WBDdx <10 (x109/L). Multivariate analysis revealed WBCmax > 43 (x109/L) and low antithrombin III were significant for DS, while old age, WBCmax, and high D-dimer were associated with early death. In our data, dexamethasone prophylaxis did not show a preventive effect for DS or early death, while leukapheresis in patients with WBCmax >43 (x109/L) showed marginally decreased early death rate `resulting superior OS without significant bleeding complications. Conclusion: Our data revealed WBCmax with higher increment ratio was a significant predictive factor for early death and DS compared to WBCdx even in the low Sanz-risk group. The role of dexamethasone, transfusion support including antithrombin III, leukapheresis or cytoreduction should be evaluated in the specific patient subset for reducing early events in APL. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2044
Author(s):  
Pierre-Yves Dumas ◽  
Sarah Bertoli ◽  
Emilie Bérard ◽  
Laetitia Largeaud ◽  
Audrey Bidet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Real World ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Hypomethylating Agents ◽  
First Line ◽  
Phase 3 ◽  
Free Treatment ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.

scholarly journals Clofarabine Plus Low-Dose Cytarabine for the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome (MDS) Who Have Been Relapsing after, or Are Refractory to, Hypomethylating Agent (HMA) Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3166-3166 ◽  
Author(s):  
Elias J. Jabbour ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Tapan M. Kadia ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Group Performance ◽  
Performance Status ◽  
Advisory Board ◽  
Cell Transplant ◽  
Complex Karyotype ◽  
Overall Response ◽  
Low Dose Cytarabine

Abstract Background: HMA therapy is standard of care for patients with MDS. Outcome post HMA failure is poor with a median survival of 4-6 months. Clofarabine is a second generation nucleoside analog with single agent activity in MDS. The objective of this phase II trial is to evaluate the safety and activity of the combination of clofarabine and low dose cytarabine in the treatment of patients with high risk MDS who failed prior HMA therapy. Methods: Eligible patients were adults older than 18 years with MDS intermediate-1 and higher by the IPSS, who have had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine. Patients were required to have an Eastern Cooperative Oncology Group performance status of </=2 at the time of study entry. Responses were defined according to International Working Group 2006 criteria. Induction therapy consisted of clofarabine 10-15 mg/m2 IV daily X 5 days (days 1-5) and cytarabine 20 mg SC twice daily X 7 days (days 1-7). Patients could receive up to 3 induction cycles as long as they tolerated the therapy and had stable disease. Responding patients proceeded with consolidation therapy with clofarabine 10-15 mg/m2IV daily X 3 days (days 1-3) and cytarabine 20 mg SC twice daily X 5 days (days 1-5) for a maximum of 12 cycles. Cycles were repeated every 4 to 8 weeks depending on hematopoietic recovery and resolution of toxicities. Results: From January 2012 to August 2015, 80 eligible patients were enrolled in this prospective study (NCT01444742) and received a median of 2 cycles (range, 1-12) (Table 1). The overall response rate (ORR) was 46% (16 [20%] achieved complete remission (CR), 17 [21%] marrow CR, 1 [1%] partial response (PR), 3 [4%] hematological improvement (HI)) with a median response duration of 7 months. The median time to response was 42 days (range, 9-191). By multivariate analysis, complex karyotype was the only independent factor predicting for response (hazard ratio [HR] 0.13; 95% confidence interval [CI]: 0.03- 0.62; p=0.01). Of the 37 patients with diploid karyotype, the overall response was 68% (7 [19%] achieved CR, 15 [41%] marrow CR, 1 [3%] PR, 3 [4%] HI). Nine of the responding patients received subsequent allogeneic stem cell transplant (ASCT). With a median follow-up of 24 months (range: 1-51 months), the median event-free survival (EFS) and overall survival (OS) times were 5 months (95% CI: 2.7-6.3) and 11 months (95% CI: 6.5-14.9), respectively (Figure 1). The median OS for responding and non-responding patients was 24 months (95% CI: 11.7-35.6) and 5 months (95% CI: 2.8-6.2), respectively (p<0.001). There was no difference in OS whether patients were censored or not at the time of ASCT (p=0.463). At last follow-up, 22 patients (28%) remained alive: 1 is receiving low-dose clofarabine and cytarabine, 5 are alive in response after ASCT, 9 are receiving salvage therapy, 1 went to hospice, and 6 were lost to follow-up. By multivariate analyses, complex karyotype, platelet count less than 30 x 109/L, and poor performance status were independently associated with poor survival. In addition, the response to the combination of low-dose clofarabine and cytarabine was independently associated with better OS (HR 0.17; 95% CI 0.09-0.36; p<0.001). Grade ≥ 3 therapy-related toxicity included infections (34%), increased liver functional tests (8%), acute renal failure (3%), skin rash (3%), syncope (1%), and rectal bleeding (1%). Twenty-two (28%) patients had clofarabine dose reduction after a median of 2 courses. After 47 patients were enrolled and several patients experienced infections during induction, the protocol was amended to reduce the dose of clofarabine to 10 mg/m2 per day for 5 and 3 days during the induction and consolidation phases, respectively. There was no difference in responses before and after the modification to the protocol's dosing schedule (p=0.314). Conclusion: The combination of low-dose clofarabine and cytarabine in patients with higher-risk MDS after HMA failure resulted in an ORR of 46% and median OS of 11 months and may be particularly effective in patients with diploid karyotype. Our results also indicate that the combination of low-dose clofarabine and cytarabine may be useful as a bridge to ASCT in eligible patients. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jain:Abbvie: Research Funding; Infinity: Research Funding; Servier: Consultancy, Honoraria; Incyte: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals First Description of Upfront Target Therapy Treating AML and Bcll Presented Simultaneously As First Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Juliana Santos Carvalho ◽  
Anna Flávia Silva Alves Silva ◽  
Maysa Coité Silva ◽  
Itala Gomes Santos ◽  
Laryssa Pinto Aragão ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Case Report ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Target Therapy ◽  
First Line ◽  
Hematological Neoplasms ◽  
Hla Dr ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

INTRODUCTION: The occurrence of acute myeloid leukemia (AML) and chronic lymphoid leukemia (B-CLL) simultaneously is rarely described. We describe a case report of AML and B-CLL, diagnosed simultaneously, without any previous treatment for any of the hematological neoplasms [1]. The patient received low-dose cytarabine (ARA-C) and Venetoclax, which is medically indicated on label for both hematological neoplasms. CASE REPORT: A 75-year-old male, presented with edema and joint pain one month before hospital admission, showing pancytopenia on a complete blood count and presence of blasts in peripheral blood. The patient was then referred to the hematology service. The morphological analysis of the bone marrow aspirate showed 67.7% of myeloblasts, compatible with AML. Bone marrow immunophenotyping was performed, which identified 34.10% of myeloblasts, compatible with AML and 50.48% of monoclonal B lymphocytes (chronic B-cell lymphoproliferative disease). In flow cytometry there were two distinct populations of myeloblasts. Type 1 myeloblasts labeling CD7 +, CD13 +, CD34 ++, CD38 ++, CD45 ++, CD56 ++, CD117 ++, CD123 +, HLA-DR +++ and MPO + / ++. The second population marked CD13 + / ++, CD34 + / ++, CD38 ++, CD45 +, CD117 ++, CD123 +, HLA-DR ++ / +++ and MPO + (30%). Monoclonal lymphocytes showed CD11c + / ++ (70%), CD19 ++, CD20 + / ++ (84%), CD22 + (39%), CD23 + / ++, CD25 +, CD31 +/-, CD43 ++, CD45 ++ / +++, CD81 + (38%), CD200 + (85%) and Lambda +. The molecular study was negative for genetic abnormalities: FLT3, KIT and NPM, configuring the patient as an intermediate risk for AML. In the cytogenetic analysis there was no growth of metaphases. Patient received simultaneous diagnosis of AML and B-CLL. As he was ineligle to intensive chemotherapy (IC), we started original protocol Subcutaneous Cytarabin+venetoclax(VIALE C). The patient had grade 2-3 AE(neutropenia managed with GCSF) ending the fourth cycle in July 2020. The evolution of hematimetric parameters and diseases are described in graphics. DISCUSSION: This is the first described case in our knowledge treated upfront with bcl2-inh target therapy for two absolutely different hematological neoplasms: AML and BCLL. Nowadays we are experiencing a new therapeutic model in oncohematology, in which the targeted therapy is gaining ground in relation to IC with excellent results. In this way, the importance of comprehension of the pathophysiological mechanism of the neoplasms and the way we can stop the disease proliferation is progressively guiding the new protocols. Elderly patients are more likely to have early treatment-related death and exhibit therapeutic resistance, limiting alternatives. We decided to start first-line treatment with ARA-C and Venetoclax [2]. Venetoclax associated with ARA-C has a manageable safety profile, producing quick and durable remissions in elderly people with AML ineligible for IC, as well as in B CLL, being the best therapeutic alternative for the case, in our opinion. Venetoclax belongs to a group of drugs called Bcl-2 inhibitors, an anti-apoptotic protein, which works by blocking this protein in the body, causing apoptosis of both neoplastic cells. The high rate of remission and low early mortality, combined with fast and durable remission, make Venetoclax and ARA-C a new and attractive treatment for the elderly [2]. In our case, the intention of the product in the first line was not B-CLL, but it would certainly be a good option for this profile of elderly patients. CONCLUSION: We report the first description of simultaneous diagnosis of AML and B CLL treated with a Bcl-2 inhibitor, demonstrating that antitumor mechanisms can be extremely effective in completely different diseases. We have a long way to go in the search for full knowledge of oncohematological diseases and targeted therapies. However, this case report shows that we are on the right track. References: 1. MUSSAED, Eman Al; OSMAN, Hani; ELYAMANY, Ghaleb. Simultaneous existence of acute myeloid leukemia and chronic lymphocytic leukemia: a case report.Bmc Cancer.Springer Science and Business Media LLC. http://dx.doi.org/10.1186/s12885-016-2780-5. 2. WEI, Andrew H.; et al. Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: results from a phase ib/ii study.Journal Of Clinical Oncology, [S.L.], 20 maio 2019. American Society of Clinical Oncology (ASCO). http://dx.doi.org/10.1200/jco.18.01600. Figure Disclosures De Queiroz Crusoe: Janssen:Research Funding.

scholarly journals Off-Label Use of Venetoclax Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia: A Single Institution Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5133-5133 ◽  
Author(s):  
Daria Gaut ◽  
Aaron Burkenroad ◽  
Tuyen Duong ◽  
Jesse Feammelli ◽  
Joshua Sasine ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Combination Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Cell Transplant ◽  
Grade 3 ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Introduction Venetoclax (VEN) is a selective BCL-2 inhibitor that has demonstrated activity against acute myeloid leukemia (AML) and has been shown to be effective when used in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) for treatment-naïve, elderly AML patients unfit for intensive chemotherapy. Data on its use in the relapsed/refractory setting is limited. Methods A retrospective analysis was performed among 12 relapsed or refractory AML patients treated with VEN combination therapy at the University of California Los Angeles from 2018-2019. Seven patients received VEN in combination with azacitidine (75 mg/m2 x 7 days), 4 patients with decitabine (20 mg/m2 x 5 days), and 1 patient with low-dose cytarabine (20 mg/m2 x 10 days). Results The median patient age at time of VEN therapy was 58 years (range 41-79). Four patients (33.3%) had secondary AML. The majority (9 patients, 75.0%) had adverse cytogenetics. Three patients (25.0%) had received an allogeneic stem cell transplant prior to VEN therapy, and 5 patients (41.7%) had failed HMA therapy prior. Notable molecular mutations present were TP53 (4 patients, 33.3%), FLT3 (3 patients, 25.0%), and IDH2 (1 patient, 8.3%). Eight patients (66.7%) had grade 3 or greater neutropenia at time of VEN initiation, and 9 patients (75.0%) had grade 3 or greater thrombocytopenia. Four patients (33.3%) had a grade 3 or greater infection prior to VEN therapy. Dosing of VEN was by physician discretion with a median starting dose of 150 mg (range 100-800) and a median maintenance dose of 450 mg (range 200-800). The median number of cycles of VEN combination therapy was 2 (range 1-5). Seven patients (58.3%) had decreased VEN dosage due to concomitant azole for antifungal prophylaxis. Four patients (33.3%) were on an additional small molecular inhibitor while receiving VEN therapy (sorafenib in 3 patients, ruxolitinib in 1 patient). The majority (10 patients, 83.3%) had an interruption in VEN dosing for the following reasons: bone marrow functional delay (7 patients), inability to tolerate oral pills (4 patients), infection (3 patients), and bleeding (2 patients). The objective response rate (ORR) was 41.7% with 3 patients (25.0%) achieving complete remission with incomplete hematologic recovery (CRi) and 2 patients (16.7%) achieving partial remission (PR) (Table 1). Three patients (25.0%) experienced early death within 30 days due to the following: pneumonia (1 patient), multi-organ failure from infection and graft-versus-host disease (1 patient), and intracranial hemorrhage (1 patient). The median time to first and best response was 56 days (range 27-101) or after approximately 2 cycles of VEN combination therapy. During VEN therapy, all patients (100%) had grade 3 or greater neutropenia and thrombocytopenia, and 10 patients (83.3%) had grade 3 or greater anemia. The nadir of most cytopenias occurred during cycle 1. Six patients (50.0%) developed a grade 3 or greater infection following VEN therapy, and 2 patients (16.7%) developed a grade 3 or greater intracranial hemorrhage. The only other notable grade 3 or greater side effects noted during VEN therapy were dizziness (1 patient, 8.3%) and diarrhea (1 patient, 8.3%). After a median follow-up time of 3.14 months (range 1.22-13.48), 2 patients (16.7%) progressed, and the 1-year progression-free survival (PFS) rate was 71.11% (95% CI 43.40-100.00) (Figure 1). Eight out of 12 patients died as a result of infection (6 patients, 50.0%), disease progression (1 patient, 8.3%), and bleeding (1 patient, 8.3%). The median overall survival (OS) was 4.74 months (range 1.18-9.15), and the 1-year OS rate was 14.60% (95% CI 2.54-83.80) (Figure 2). VEN was discontinued in all patients because of no response (5 patients, 41.7%), adverse effects (4 patients, 33.3%), transition to donor lymphocyte infusion (1 patient, 8.3%), or transition to allogeneic stem cell transplant (2 patients, 16.7%). Conclusions We present our institutional experience with VEN combination therapy for the treatment of relapsed/refractory AML with a particularly high-risk patient cohort, predominantly characterized by adverse genetic features and grade 3 cytopenias prior to start of therapy. Overall, the response rate was modest, but not inferior to that with conventional salvage chemotherapy. Adverse events were primarily due to pre-existing bone marrow failure, likely exacerbated by treatment. Disclosures Schiller: Agios: Research Funding, Speakers Bureau; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. It does not currently have an approved use for the treatment of acute myeloid leukemia in the relapsed/refractory setting.

scholarly journals Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged ≥65 Years with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 102-102 ◽  
Author(s):  
Andrew Wei ◽  
Stephen A. Strickland ◽  
Gail J. Roboz ◽  
Jing-Zhou Hou ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Safety And Efficacy ◽  
Treatment Naïve ◽  
The Mean ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

Abstract Background: Multiple studies have demonstrated the modest efficacy of low-dose cytarabine (LDAC) in older patients (≥65 years) with Acute Myeloid Leukemia(AML) who are unlikely to benefit from an anthracycline and cytarabine intensive induction [CR/CRi rates of 10 - 26%; (CRi = complete remission with incomplete marrow recovery)]. Venetoclax, a selective BCL-2 inhibitor has demonstrated single-agent activity in patients with relapsed and refractory AML [Konopleva et al., ASH 2014]. When administered with LDAC, the recommended phase 2 dose (RP2D) of venetoclax was 600 mg daily [Lin et al., ASCO 2016 (abstract 7007)]. Here we present the safety and efficacy data at RP2D of venetoclax from the dose escalation and expansion phases of the study (NCT02287233). Methods: Patients enrolled as of 15DEC2015 are included in this analysis with a data cut-off date of 31MAR2016. Patients were eligible if considered unfit for intensive chemotherapy, had an ECOG performance status of 0-2 and adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder, or those with acute promyelocytic leukemia or active CNS involvement with AML were excluded from the study. Venetoclax 600 mg was administered orally once daily on days 2 - 28 of Cycle 1 and days 1 - 28 of subsequent cycles. A 5-day dose ramp-up schedule was followed to reach the 600 mg dose. LDAC 20 mg/m2 was administered s.c. daily on days 1-10 in 28-day cycles. To mitigate the potential risk of tumor lysis syndrome (TLS), all patients were hospitalized and received prophylaxis commencing 48 hours prior to venetoclax during Cycle 1. Adverse events (AEs) were graded by NCI CTCAE Version 4.0. Results: Twenty patients were enrolled in the study (escalation, n=8; expansion, n=12). The median age was 74 years (range: 66 - 87). 8/20 (40%) patients had an antecedent hematologic disorder. Median time on venetoclax was 147.5 days (range: 8 - 455). Grade 3/4 AEs (≥10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. Venetoclax exposures on Cycle 1 Day 10 (with LDAC) vs. Cycle 1 Day 18 (venetoclax alone) were comparable. The mean ± SD of maximum observed concentration (Cmax, µg/mL/mg) were 2.04 ± 1.45 vs. 2.92 ± 2.15, respectively. The mean ± SD of area under the curve (AUC24, µg*hr/mL) were 33.3 ± 27.5 vs. 46.1 ± 36.8, respectively. Similarly, co-administration of venetoclax did not markedly affect LDAC exposures. The mean ± SD of Cmax (ng/mL) of LDAC on Cycle 1 Day 1 (LDAC alone) vs. Cycle 1 Day 10 (with venetoclax) were 158.89 ± 79.08 vs 166.49 ± 32.06, respectively. Similarly, the mean ± SD of AUCinf (ng*hr/mL) were 170.64 ± 102.86 vs 246.51 ± 93.41, respectively. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI=49.4 - 88.6) and that for the responders (n=15) was 86.7% (95% CI=56.4 - 96.5). The overall response rates and 12-month OS estimates for patients with or without prior hypomethylating agent (HMA) and with or without MPN are summarized in Table 1. A Kaplan-Meier curve showing OS for responders vs. non-responders is shown in Figure 1. The median time to best response was 30 days (range: 23 - 169). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. Conclusions: Venetoclax (600 mg RP2D) plus LDAC demonstrated an acceptable safety and pharmacokenitic profile in patients aged ≥65 years with treatment-naive AML who are not eligible for an intensive anthracycline-containing induction chemotherapy. Clinical remission was achieved in the majority of patients. The median OS has not been reached. A substantially better survival in responders as compared to non-responders suggests that the improvement is likely due to treatment with venetoclax plus LDAC. Updated responses and survival estimates for all patients, including those in dose expansion phase that were enrolled after the preliminary data cut, will be presented. Disclosures Wei: Novartis: Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sanofi: Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Kolltan: Research Funding; Novartis: Consultancy; Teva: Other: Travel; Ariad/Incyte: Consultancy; Gilead: Other: Travel; Pfizer: Research Funding; GSO: Other: Travel. Martinelli:MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; BMS: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Fakouhi:AbbVie Inc.: Employment, Other: may own stock. Darden:AbbVie Inc.: Employment, Other: may own stock. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Agarwal:AbbVie Inc.: Employment, Other: may own stock. Salem:AbbVie Inc.: Employment, Other: Stocks or options. Mabry:AbbVie Inc.: Employment, Other: May own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock.

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