Mutant NPM1 is a Reliable marker of Minimal Residual leukemia in patients with Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2484-2484
Author(s):  
Preetesh Jain ◽  
Hagop M. Kantarjian ◽  
Stefan Faderl ◽  
Keyur P. Patel ◽  
Guillermo Garcia Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
De Novo ◽  
Response Rates ◽  
Analytical Sensitivity ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Npm1 Mutation ◽  
De Novo Aml ◽  
Minimal Residual

Abstract Abstract 2484 Background: Mutations in NPM1 (Nucleophosmin-1) have been described in about 35% of adult patients with de novo AML and 45–60 % of AML patients with a diploid karyotype. NPM1 mutations predict for achieving higher complete remission (CR) rates and better outcomes in AML. Few studies have reported on the reliability of mutated NPM1 as a marker for minimal residual disease (MRD) detection in patients with AML. Methods: We conducted a retrospective analysis of patients (n=360) with newly diagnosed AML treated at our institution between 2008 and 2012. The study was approved by the Institutional Review Board. NPM1 mutation status was determined from DNA from unsorted bone marrow (BM) aspirate samples by a PCR-based method at baseline, remission, and relapse. Genomic DNA from bone marrow samples was isolated using the Autopure extractor (QIAGEN/Gentra, Valencia, CA). Mutations in exon 12 of NPM1 were assessed by a DNA-based semi-quantitative polymerase chain reaction capillary electrophoresis (PCR-CE) assay with analytical sensitivity of approximately 2.5%. Results: Data on remission and relapse samples from 360 newly diagnosed and previously untreated patients with AML, with available NPM1 analysis on their BM at the time of initial diagnosis, was collected (see flow chart below). Median age was 60 years (range 21 – 81 years). 262 patients (72%) had de novo AML, and 98 (27%) secondary AML. Cytogenetics was diploid in 137 (38%) patients, t(8;21) in 17 (5%), inversion 16 in 26 (7%), deletion 5 alone in 27 (7.5%), del 7 and 5 in 26 (7%), deletion 7 alone in 21 (5.8%), trisomy 8 in 17 (5%) and miscellaneous in 89 (24.7%) patients, respectively. Overall, 60 (16.6%) patients including 46 of the 137 (33.5%) diploid patients had NPM1 mutation at baseline. Secondary leukemia was more common in the NPM1 wild type (30%) than in the NPM1 mutated (13%) category. When analysed by age, in patients < 60 years (n=175), OS (overall survival), EFS (event free survival) and response rates were significantly superior in NPM1 mutated subgroup (p=0.001, 0.007, 0.02 respectively), while among patients ≥ 60 years (n=185) EFS and response rates were significantly higher in the NPM1 mutated subgroup (p=0.008, 0.03 respectively). Among the patients with diploid cytogenetics who were younger than 60 years (n=60) OS, EFS and CR duration was significantly better in the NPM1 mutated subset (p=0.007, 0.007 and 0.02 respectively), while in those ≥60 years (n=77) there was no statistically significant difference in the outcomes for the NPM1 mutated and wild-type subsets. Among the 60 NPM1 mutated patients 54 (90%) including 41/46 (89%) of those with diploid cytogenetics achieved complete response (CR) or CR without platelet recovery. Thirty nine patients (including 30 with diploid karyotype) had available NPM1 status at the time of CR and all (100%) were negative for NPM1 mutation. Among the patients with mutated NPM1 at baseline who have achieved a NPM1 negative status at CR, 10/39 overall (25%) and 7/30 diploid (23%) patients relapsed. NPM1 status was available for 6 patients overall including 4 with diploid karyotype at the time of relapse. Among them, 5/6 overall (83%) and 3/4 diploid (75%) patients had mutated NPM1, while 1/6 overall (16%) and 1/4 diploid (25%) patients remained NPM1 wild type. This patient relapsed with extramedullary disease (leukemia cutis) without any BM involvement. Among the 300 patients (including 91 with diploid karyotype) with wild type NPM1 at diagnosis, none acquired a mutated NPM1 clone, either at CR or at the time of relapse. Conclusions: These data suggest that mutated NPM1 is a reliable and stable marker for the detection of MRD at the time of CR. Hence, NPM1 mutations can be used to detect MRD and their recurrence may predict pending relapse. Disclosures: Cortes: Celgene: Research Funding. Ravandi:Johnson and Johnson: Honoraria; Celgene: Research Funding.

scholarly journals Molecular Patterns of Response and Outcome in the Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT study)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 333-333 ◽  
Author(s):  
Andrew H Wei ◽  
Chong Chyn Chua ◽  
Ing S Tiong ◽  
Chun Yew Fong ◽  
Stephen B Ting ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Elderly Patients ◽  
Advisory Committee ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
De Novo ◽  
Response Rates ◽  
Advisory Board ◽  
Assay Sensitivity ◽  
De Novo Aml

Abstract Background: Venetoclax (VEN) is a potent small molecule BH3-mimetic drug that selectively targets the prosurvival protein BCL-2 and has an emerging role for treatment in Acute Myeloid Leukaemia (AML). This ongoing Phase 1b study aims to evaluate the optimal dose, safety and efficacy of VEN in combination with modified intensive chemotherapy in fit, elderly patients with AML who have not received prior induction chemotherapy. Here we present updated data including molecular correlates of response and treatment outcomes. Methods: Eligibility: Patients were enrolled with AML (excluding APL), age ≥65 years (≥60 years if monosomal karyotype), ECOG 0-1 and adequate organ function. Prior HMA/LDAC was permitted after a 14-day washout. Treatment: 1) Dose escalation cohorts comprised VEN 50mg (Cohort A), 100mg (B), 200mg (C), 400mg (D) or 600mg (E); 2) a 7-day VEN pre-phase incorporating dose ramp-up to minimise tumour lysis risk followed by a 7-day overlap with chemotherapy (day -6 to +7); 3) attenuated induction chemotherapy with cytarabine 100mg/m2/day IVI d1-5 staggered with idarubicin 12mg/m2 IV d2-3. For patients in remission, 4 cycles of consolidation were administered, comprising 14 days of VEN (day -7 to +7) with bolus cytarabine (100mg/m2/day IV d+1-2) and idarubicin (12mg/m2 IV d+1) followed by 7 cycles of VEN monotherapy maintenance; planned to commence q28d. Antifungal azoles were avoided during VEN exposure. The first patient was enrolled 17JUL2016. Molecular studies- Next generation sequencing using a 54-gene TruSight myeloid panel was performed on baseline bone marrow samples. FLT3-ITD testing was performed by capillary electrophoresis. RT-qPCR was used to detect minimal residual disease (MRD) in NPM1-mutated cases (assay sensitivity: 10-5-10-6). Results: The data cut-off date was 13JUL2018. 44 patients were enrolled with 3 patients still in the induction cycle. Median age was 72 years (range 63-80 years; 23% ≥75 years), 66% of patients were male, 41% had secondary AML and 38% prior hypomethylating agent (HMA) exposure. Main grade ≥3 non-haematological adverse events during induction were febrile neutropenia (56%), sepsis (32%), rapid atrial fibrillation (15%), diarrhoea (12%), nausea (10%) and localised infection (10%). No clinical TLS was observed. One hematologic dose-limiting toxicity was reported in cohort E (VEN 600mg), but a maximum tolerated dose has not been reached. We observed progressive delay in platelet count recovery as patients proceeded with each cycle of therapy (median time to platelets ≥50x109/L was 25d in induction, 37d in consolidation 1 and 57d in consolidation 4). Treatment-related mortality was 7% in induction. 18/38 (47%) had ≥30% relative reduction in bone marrow (BM) blasts after 7 days of pre-phase VEN monotherapy, with no correlation between VEN dosage and the degree of BM blast reduction. Overall CR/CRi rate was 71%. CR/CRi was achieved in 95% of patients with de novo AML (vs 42% in secondary/therapy-related AML). Response rates were 88% in intermediate vs 46% in adverse cytogenetic risk AML. Responses in patients with prior HMA therapy were 43% and 84% for previously untreated patients. Molecular data were available for 41 patients. 98% had ≥1 mutation detected. (Figure 1) Responses in response-evaluable patients were most common in NPM1 mutant AML (100%; n=7), followed by RUNX1 (90%; n=11), RAS (90%; n=10) and IDH (89%; n=9). Lowest responses were observed in TP53 mutant AML (33%; n=9). NPM1 MRD assessment was performed on 6 patients, of which 5 (83%) achieved NPM1 MRD negativity. (Figure 2) Updated response, response duration and survival data will be presented, along with molecular characteristics of relapse. Conclusion: To date, VEN up to 600mg in combination with 5+2 induction chemotherapy is tolerable in fit elderly patients with AML. Initial response rates >80% were observed in de novo AML, as well as NPM1, RUNX1, RAS and IDH mutant AML, whereas responses were lower in patients with prior HMA exposure, adverse karyotype, secondary and TP53 mutant AML. Molecular determinants of relapse require further study. Disclosures Wei: Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Amgen: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Fong:Celgene: Other: Advisory board; Novartis: Other: Advisory board; Amgen: Research Funding; Pfizer: Other: Speaker fees. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Roberts:Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Study of Sequential Treatment of Newly Diagnosed De Novo AML Patients with DA and CAG Regimens as Remission Induction Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4630-4630
Author(s):  
Hui ping Sun ◽  
Wei Hong Liu ◽  
Jun min Li ◽  
Qiu sheng Chen ◽  
Yu Chen
Keyword(s):  
Bone Marrow ◽  
Induction Therapy ◽  
Peripheral Blood ◽  
De Novo ◽  
Classification Criteria ◽  
Sequential Treatment ◽  
Remission Induction ◽  
Newly Diagnosed ◽  
Fab Classification ◽  
De Novo Aml

Abstract Objectives To evaluate the efficacy and safety of sequential treatment of newly diagnosed de novo AML patients with DA and CAG regimens as induction therapy. Methods Those who were newly diagnosed as de novo AML (FAB classification criteria) were enrolled and DA regimen chemotherapy were administered. Bone marrow aspirates were performed and BM smears were examined at 48 hours since the end of chemotherapy. If severe hypocellularities were not achieved, the percentage of blasts in BM was between 20%–60% and peripheral WBC was in the range of (0.5–10) x109/L, the patients would receive CAG regimen therapy since 72 hours. Patients’ general status and the important parameters, such as peripheral blood count, liver function, renal function, thrombosis and hemostasis parameters were monitored throughout the course of the treatment and thereafter. When the clinical symptoms were relieved and peripheral blood counts returned to normal, or it was the end of the second or third week since the end of the CAG regimen, Bone marrow were examined again to evaluate the efficacy of the sequential therapy. Results 14 patients consisted of 9 male and 5 female patients were enrolled. Out of them, 2 were M1, 5 M2, 4 M4 and 3 M5 according to FAB classification criteria. Median of blasts in BM were 38.5%(20%–60%) before CAG regimen. Of the 14 patients, 10 reached CR, 2 PR and 2 NR. CR rate was 71.4% (10/14) and total response rate was 85.7%(12/14). Time to achieve CR was on 15th(14th–29th)day medianly since the end of the treatment. During the CAG therapy courses, the nadir of peripheral blood cell counts and the time when it occurred were as follows: WBC 1.0(0.2–3.5)(x109/L),10(1–23)(d); Hb 57.5(44–69) (g/L), 10(1–27)(d)and PLT 11.5(10–65)(x109/L), 12(3–23)(d), respectively. Neutropenia (WBC<1.0x109/L) and thrombocytopenia (PLT<20.0x109/L) were lasted for 0(0–24) and 11(0–21)days, respectively. Median units of transfusions of platelets and red blood cells required by each patient were 3(0–10)(u) and 4(0–12)(u), respectively. The most commonly observed side effect of the regimen was bone marrow proliferation inhibition. Infections, usually respiratoy tract infections, were the second. However, sepsis was rare, which appeared in 1 out of 14 patients. Conclusions DA and CAG regimens sequential treatment as remission induction chemotherapy in patients with newly diagnose de novo AML was highly effective and well tolerated. It would be beneficial for those who might not be sensitive enough to DA regimen chemotherapy only.

Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2481-2481
Author(s):  
Courtney D. DiNardo ◽  
Ross L. Levine ◽  
Kathleen J Propert ◽  
Alison W. Loren ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Mutational Analysis ◽  
Eastern Cooperative Oncology Group ◽  
Elevated Serum ◽  
Wild Type ◽  
Serum Samples ◽  
Prognostic Information ◽  
Idh Mutations ◽  
De Novo Aml

Abstract Abstract 2481 Purpose: Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival. Patients and Methods: Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS). Results: Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p &lt; 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels &gt;700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1). Conclusion: We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies. Disclosures: Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.

scholarly journals Retrospective Analysis of Adults with Acute Myeloid Leukemia Treated with Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1424-1424 ◽  
Author(s):  
Matthew Tenold ◽  
Benjamin Moskoff ◽  
David Benjamin ◽  
Brian A. Jonas
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Response Rates ◽  
Median Number ◽  
Adult Patients ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Hypomethylating Agents ◽  
De Novo Aml

Abstract Introduction Venetoclax (VEN) is a potent B-cell lymphoma 2 (BCL-2) inhibitor and demonstrates synergistic anti-AML activity when used in combination with hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC). This regimen has demonstrated high response rates and durable activity in treatment naïve (TN) older patients; however, the efficacy in relapsed and/or refractory (R/R) AML is less well characterized, with one study showing a response rate of 21%. To further characterize VEN plus HMA activity in these populations, we retrospectively reviewed the outcomes of both TN and R/R AML patients treated with VEN plus HMA at the University of California Davis Comprehensive Cancer Center (UCDCCC). Methods Adult patients (≥18 years) with an acute leukemia treated with VEN off protocol between January 1, 2014 through June 22, 2018 were included. Under an IRB-approved protocol, patients were retrospectively reviewed using an electronic medical record generated report. Baseline data included patient demographics, performance status, disease characteristics, prior chemotherapy, bone marrow biopsy studies and labs. Regimen data included other chemotherapy agents received, VEN dose and modifications, antifungal prophylaxis (ppx), and granulocyte colony stimulating factor (GCSF) use. Efficacy outcomes included complete remission (CR), CR with incomplete count recovery (CRi), composite CR (cCR, defined as CR + CRi), morphologic leukemia free state (MLFS), overall leukemia response (OLR, defined as cCR + MLFS), overall survival (OS), and relapse free survival (RFS). Toxicity outcomes were reviewed, including tumor lysis syndrome (TLS), febrile neutropenia (FN), and prolonged pancytopenia. All follow-up clinic visits, hospitalizations and deaths were reviewed. Results Forty-two patients were included (AML, n=41; acute undifferentiated leukemia, n=1). Median age was 67 years [25-88] and 67% were male. Eighteen (43%) had de novo AML, 17 (40%) had preceding myelodysplastic syndrome (MDS), 4 had MDS/myeloproliferative neoplasm (MPN) (10%) and 3 (7%) had primary myelofibrosis. Sixteen were TN (38%), thirteen (31%) had relapsed disease, and 13 (31%) had refractory disease. Median number of prior regimens was 1 [0-6]. Thirty-seven (88%) had an ECOG of 0 to 1 [0-3]. ELN genetic risk classification was intermediate in 19 (45%) and adverse in 22 (52%). VEN was combined with AZA in 12 (29%) and DEC in 30 (71%). Median VEN dose was 400 mg [50-800 mg]. Median follow-up was 17.2 months. For the entire study, the cCR was 43% and the OLR was 57%. See table 1 for cCR and OLR for subgroups including previously untreated, R/R, de novo, secondary AML (sAML), and various molecular and cytogenetic subgroups. Median OS was 6.2 months (Figure 1). For patients with cCR, OLR, and MLFS, median survival was 21.6, 15.1, and 4.9 months respectively (Figure 2). Median OS and median OS in responders for patients with de novo AML, sAML, untreated patients, and R/R patients is shown in Figure 3, Figure 4, and Table 1. Median number of cycles for cCR was 1 [1-6]. Of patients who obtained cCR, 6 (33%) experienced relapse of AML. Median time to relapse was 6.6 [3.4-13.9] months. Eight (19%) patients were bridged to allotransplant. Lab TLS occurred in 1 patient. Seventeen (40%) experienced prolonged pancytopenia. Eighteen (43%) had FN and 4 (22%) received GCSF. Antifungal ppx was used in 41 (98%) patients: micafungin in 17 (40%) and a non-fluconazole azole in 24 (57%). Seven (17%), of which 5 (71%) had R/R AML, were diagnosed with a fungal infection; 5 (71%) were receiving ppx azoles and 2 (29%) micafungin. Three and 6 died within 30 and 60 days of therapy initiation, respectively; all 3 patients who died within 30 days had R/R AML. The most common cause of death was refractory AML at 14 (52%) followed by infection in 9 (33%). Conclusion At UCDCCC, VEN in combination with an HMA is well tolerated and produces high rates of response in adult patients with AML. Response rates for TN AML, sAML and multiple molecular subgroups are consistent with prior reports, while higher than expected response rates and survival were seen in R/R AML. Responses were also seen in post-MDS/MPN and post-MF patients. In extended follow-up, survival has been durable in patients with cCR, but not MLFS. The use of VEN plus HMA combinations in adults with AML represents a viable treatment option for both TN and R/R AML. Disclosures Jonas: AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Glycomimetics: Research Funding; Pharmacyclics: Research Funding; Tolero: Consultancy; Amgen: Consultancy; Forma: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Kalobios: Research Funding; Accelerated Medical Diagnostics: Research Funding; LP Therapeutics: Research Funding.

scholarly journals The Presence of Minimal Residual Disease, As Determined By Highly Sensitive Quantitation of NPM1-Mutatation, Provided Powerful Prognostic Information in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5097-5097
Author(s):  
Atsushi Marumo ◽  
Hiroki Yamaguchi ◽  
Yuho Najima ◽  
Kensuke Usuki ◽  
Shinichi Kako ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Minimal Residual ◽  
Hematological Remission ◽  
Acute Myeloid

Background: As recurrence of acute myeloid leukemia (AML) is difficult to predict, it is important to detect it by measuring minimal residual disease (MRD). PML-RARA, RUNX-RUNX1T1, CBFB-MYH11 are regarded as the reliable MRD markers. However, in AML with normal karyotype and many other forms, no MRD markers have been established. NPM1 mutations, occurring in approximately 30% of adult AML cases, and 50-60% of AML cases with normal karyotype, represent one of the most frequent mutations in AML. Recently, NPM1 mutation is reported to be useful in assessing MRD. We undertook a retrospective and prospective investigation of the usefulness of NPM1 mutation as an MRD marker in Japanese patients with AML. Methods: The subjects were 38 NPM1-mutated AML patients with first hematological remission at several hospitals related to our institution between 2001 and 2018. This study was approved by the ethics committee of Nippon Medical School and the informed consents were obtained from all patients, according to the Declaration of Helsinki. We analyzed peripheral blood cells or bone marrow cells at diagnoses, and evaluated only bone marrow cells after diagnoses. Detection of NPM1 mutation was carried out using allele-specific real time PCR following creation of a complementary primer. After dilution of the samples, sensitivity to TCTG, CATG, and CCTG was found to be 0.001%. The NPM1 mutant copies were qualified only at successful amplification of internal control. Results: The median age of the patients was 58 years (18-79 years). There were 32 cases with intermediate cytogenetic prognosis and 6 cases with unclear chromosomal profile. Of the 38 cases, 14 cases (37%) were FLT3-ITD-positive and allogeneic hematopoietic stem cell transplantation was carried out in 14 cases (37%). The base sequence was TCTG in 36 cases and CCTG in 2 cases. Persistence of NPM1-mutatation was present in 25 patients with first hematological remission (66%). Compared with patients with MRD negative, patients with MRD positive were associated with DNMT3A mutation (MRD positive 12/25 vs MRD negative 0/13, p=0.003). The rate of relapse in patients with MRD positive was significantly higher than those of in patients with MRD negative (MRD positive 76% vs MRD negative 23%, p=0.004). The rates of relapse free survival (RFS) and overall survival (OS) in patients with MRD positive were significantly lower than those in patients with MRD negative (RFS at 2 years: MRD positive 14% vs MRD negative 86% p=0.003; Figure 1, OS at 2 years: MRD positive 25% vs MRD negative 93%, p<0.001). In FLT3-ITD negative group, the rates of RFS in patients with MRD positive were significantly lower than those in patients with MRD negative. (RFS at 2 years: MRD positive 21% vs MRD negative 92% p=0.001; Figure 1). Conclusion: The presence of MRD with NPM1 mutation is significantly associated with relapse and it is useful to decide their treatment strategy. Especially, there is the usefulness of NPM1 mutation as an MRD marker in NPM1 positive Flt3-ITD negative AML patients who are generally classified as favorable risk. According to previous reports, it is known that NPM1-mutated AML sometimes relapse with losing NPM1 mutations. However, in this study, all NPM1-mutated AML relapse without losing NPM1 mutations. We need to collect more patients and are going to confirm whether there are patients who relapse with losing NPM1 mutations or not. We plan to analyze the genetic background of MRD positive and negative patients with next-generation sequencing. We are going to announce the genetic characteristics in addition to this result at ASH. Disclosures Usuki: Astellas Pharma Inc: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau. Kako:Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

scholarly journals Final Safety and Efficacy Results from the CPX-351 Early Access Program (EAP) for Older Patients with High-Risk/Secondary Acute Myeloid Leukemia (sAML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1434-1434
Author(s):  
Gail J. Roboz ◽  
Melissa L. Larson ◽  
S. Eric Rubenstein ◽  
Scott R Solomon ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Research Funding ◽  
De Novo ◽  
Newly Diagnosed ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Equity Ownership ◽  
De Novo Aml

Abstract Background: CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. In a large randomized, open-label, multicenter, phase 3 study of CPX-351 versus conventional cytarabine/daunorubicin chemotherapy (7+3 regimen) in adults aged 60-75 years with newly diagnosed high-risk/sAML, patients treated with CPX-351 had significantly longer survival times and higher remission rates (Lancet JE, et al. J Clin Oncol. 2018). Based on these results, CPX-351 was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (AML-MRC). This abstract reports the results of an EAP study that provided expanded access to CPX-351 for older patients who met the eligibility criteria for the phase 3 study and collected additional data on safety and efficacy. Methods: In this phase 4, single-arm, open-label EAP, patients were between 60-75 years of age and had confirmed high-risk/sAML (therapy-related AML [tAML], AML with a history of myelodysplasia [MDS] or chronic myelomonocytic leukemia [CMML], or de novo AML with MDS karyotype). Patients could receive up to 2 cycles of induction with CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) on Days 1, 3, and 5 (2nd induction: Days 1 and 3). Patients with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 4 cycles of consolidation with CPX-351 65 units/m2 (cytarabine 65 mg/m2 + daunorubicin 28.6 mg/m2) on Days 1 and 3. The primary endpoint was safety, and the secondary endpoint was the rate of CR+CRi. Results: Overall, 52 patients received ≥1 dose of CPX-351 and were included in the safety analysis. Among these patients, the median age was 70 years (range: 55-75) and 23% had an Eastern Cooperative Oncology Group score of 2. Median time since diagnosis was 0.30 months (range: 0.03-36.14) months. Patients with AML-MRC accounted for 77% of the safety analysis population, including those with antecedent MDS with prior hypomethylating agent (HMA) treatment (25%), antecedent MDS without prior HMA treatment (21%), antecedent CMML (8%), and de novo AML with MDS karyotype (23%); 23% of patients had tAML. All patients received 1 induction cycle and 25% received 2 induction cycles; 17%, 8%, 4%, and 2% of patients received 1, 2, 3, and 4 consolidation cycles, respectively. CR+CRi was achieved in 23 patients (44% [95% CI: 31%, 59%]), including 15 with CR (29% [95% CI: 17%, 43%]) and 8 with CRi (15% [95% CI: 7%, 28%]; Table). The median time to remission was 37 days (range: 15-72). At the end of the study, 47 (90%) of patients were still alive and 11 (21%) patients received transplant. All patients were alive at Day 30, and the mortality rate at Day 60 was 6%. The safety profile observed in this EAP study was consistent with that of the phase 3, randomized study (Table). Treatment-emergent adverse events (TEAEs) of any grade occurred in 96% of patients, including 44% of patients with an TEAE deemed related to treatment; the only treatment-related AE that occurred in >10% of patients was febrile neutropenia (31%). Only 2 patients (4%) discontinued treatment due to an AE (ejection fraction decrease and intercranial hemorrhage [n = 1 each]). Five patients (10%) had grade 5 AEs during the study, including disease progression, multiple organ dysfunction syndrome, acute respiratory distress syndrome, aspiration, and intracranial hemorrhage (n = 1 each). Conclusions: The data from this EAP study were consistent with results from the randomized, phase 3 study. The safety profile in the EAP study was similar to that observed in the phase 3 study and there was a similar CR+CRi rate (44% vs 48%, respectively) in this high-risk/sAML population. Disclosures Roboz: Sandoz: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Bayer: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Pfizer: Consultancy. Rubenstein:Alexion: Consultancy, Honoraria, Speakers Bureau; Cyclacel: Other: Travel support; Astex: Other: Travel support. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. An:Jazz Pharmaceuticals: Employment. Mancino:Jazz Pharmaceuticals: Employment. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Lin:Jazz Pharmaceuticals: Honoraria.

Association Between Imatinib (IM) Transporters and Metabolizing Enzymes Genotype and Response in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients (Pts) Is Influenced by Ethnicity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3283-3283
Author(s):  
Simona Soverini ◽  
Sabrina Angelini ◽  
Eleonora Turrini ◽  
Fabrizio Pane ◽  
Fabrizio Quarantelli ◽  
...  
Keyword(s):  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Wild Type Allele ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Metabolizing Enzymes ◽  
Optimal Response ◽  
Type Allele ◽  
Individual Snps

Abstract Abstract 3283 Poster Board III-1 IM is the first-choice treatment in CML and allows to obtain excellent response rates. Some pts, however, experience suboptimal response or resistance, which highlights the need to find biological predictors of outcome in order to guide therapy optimization. Since blood and tissue concentrations of drugs may be influenced by variations between individuals (single nucleotide polymorphisms, SNPs) in genes encoding drug metabolizing enzymes and drug transporters, we have investigated if SNPs influencing the delivery if IM to target cells may account for differences in response. To test that hypothesis, we have genotyped a panel of SNPs known to affect the activity of the cytochrome p450 family isoforms and of the transporters that have been implicated in IM metabolism and transport in a subset of pts enrolled in the TOPS trial -; a randomized phase III study of IM 400 mg/d vs IM 800 mg/d in newly diagnosed CML (Cortes et al, ASH 2008). Included in this analysis were 18 SNPs in 7 genes: hOCT1 (ins/del, rs12208357, rs683369, rs4646277, rs4646278, rs2282143); ABCB1 (rs60023214, rs1128503, rs10245483, rs3213619, rs1128501), ABCG2 (rs2231137, rs2231142); OCTN1 (rs1050152); OATP1A2 (rs11568563); CYP3A5 (rs28365083, rs776746); CYP3A4 (rs28371759). Genotype distributions were tested for Hardy-Weinberg equilibrium (HWE). Additive models were used to assess association between individual SNPs and three response outcomes: major molecular response (MMR) at 12 months, optimal CgR and optimal response as defined by European LeukemiaNet (ELN) recommendations (Baccarani, Blood 2006). Summary measures based on SNPs from the same gene and those related functionally (uptake and efflux) were defined as the number of alleles, across the genes of interest, hypothesized to be associated with favorable response. Association of individual SNPs and summary variables with response was assessed with logistic regression models and likelihood ratio and exact tests. A total of 166 pts were genotyped, out of which 133 whites from Italy (N=21), the U.S.A. (N=66) and Australia (N=46); 22 Asian from Korea (N=17), Italy (N=1), and Australia (N=4); and 11 non-white and non-Asian from the U.S.A (N=6) and Australia (N=5). Selection of pts was based exclusively on availability of a written informed consent for correlative substudies and of a sufficient amount of archived DNA material. The response rates by 12 months among the subset of pts analyzed were 51% for MMR, 87% for optimal cytogenetic response according to ELN, and 85% for optimal response according to ELN. Our analyses have identified four monomorphic, non-informative SNP ( hOCT1: rs4646278, rs2282143; MDR1: rs1128501; and CYP3A4: rs28371759). The results have shown, when analyzing the patient population as a whole, that no association could be found between individual SNPs and any of the response variables considered. However, among whites, but not other pts, we have observed a trend of association between achievement of MMR and two SNPs in the hOCT1 and CYP3A5 genes. Namely, the wild type allele for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (60% vs 36%, p=0.057). Also, the mutant allele for CYP3A5 rs28365083 was associated with a higher response rate (p=0.058). In the subset of pts from the U.S.A, there was a evidence of association between achievement of MMR and three SNPs in the hOCT1 and MDR1 genes. Those with the wild type allele for hOCT1 ins/del had a lower MMR rate compared to those carrying at least one minor allele (48% vs 81%, p=0.08). The wild type for hOCT1 rs683369 was associated with a higher response rate compared to heterozygote and homozygote mutants (65% vs 36%, p=0.05). MDR1 rs60023214 (p=0.08) and the MDR1 gene summary measure of total number of favorable alleles among all MDR1 SNPs (p=0.08) were correlated with MMR, with improved response in the wild type group. Our study suggests for the first time a role of ethnicity in determining correlations between SNP-based molecular signature and response to treatment. If confirmed by larger studies, this suggests that ethnicity should be taken in consideration to better interpret pharmacogenetic analyses in CML and could explain the differences in results of the studies published so far. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: White: Novartis and Britol-Myers Squibb: Research Funding. Baccarani:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.

scholarly journals Frontline Selinexor and Chemotherapy Is Highly Active in Older Adults with Acute Myeloid Leukemia (AML)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Timothy S. Pardee ◽  
Kristin M. Pladna ◽  
Susan Lyerly ◽  
Sarah Dralle ◽  
Megan Manuel ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Preclinical Studies ◽  
Newly Diagnosed ◽  
Highly Active ◽  
De Novo Aml ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by resistance to treatment and dismal outcomes, especially in the elderly. Novel approaches are desperately needed. Exportin 1 (XPO1) is involved in the selective nuclear export of certain proteins and RNA species. It is overexpressed in a subset of AML, conferring an adverse prognosis. Selinexor is a small-molecule inhibitor of XPO1 with activity in AML. Selinexor sensitizes AML cells to anthracyclines by retaining topoisomerase II in the nucleus resulting in increased DNA strand breaks. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in AML. This abstract reports the ongoing results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML, 60 years of age or older and preclinical studies to assess the mechanisms of chemo-sensitization. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized 3:1 between 7+3+selinexor or 7+3. Responding patients could go on to high dose cytarabine consolidation with or without selinexor as per initial randomization. Patients in the selinexor arm who completed all consolidation could then move to maintenance therapy with selinexor alone. Induction consisted of cytarabine 100 mg/m2/d by continuous infusion for 7 days and daunorubicin 60 mg/m2 on days 1-3. Consolidation consisted of cytarabine at 1.5 gm/m2 given Q12 hours days 1-3 with G-CSF given 24 hours following the last dose of cytarabine. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days during maintenance. Preclinical studies were conducted with murine AML cell lines. Results: Twenty-seven of a planned twenty-eight patients were enrolled to date. Of the 27 evaluable patients, 20 were randomized to the selinexor arm and 7 to the control arm. Baseline demographics are listed in Table 1. In the standard arm, both 30- and 60-day mortality were 14% (1/7). In the selinexor arm, both 30- and 60-day mortality were 10% (2/20). In the standard arm, 43% (3/7) of patients achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi). Of the 3 responders 1 has gone on to transplant. In the selinexor arm, 85% (17/20) of patients achieved a CR or CRi. Of the 17 responders, 4 have gone on to transplant. Progression free and overall survival both favor the selinexor arm with trends towards significance despite the small size of the trial (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. Selinexor induces retention of topoisomerase II in the nucleus increasing sensitivity to anthracyclines. To determine if selinexor sensitized to cytarabine viability assays using murine AML cell lines were done (Figure 2A). Selinexor significantly sensitized both cell lines to cytarabine. AML cells increase mitochondrial oxygen consumption in response to cytarabine leading to resistance. The ability of selinexor to interfere with this response was assessed using Seahorse flux analysis. AML cells treated with cytarabine for 16 hours showed a diminished mitochondrial oxygen response when co-treated with selinexor (Figure 2B). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older patients with de novo AML. Selinexor may increase response to cytarabine by interfering with nuclear-mitochondrial communication. Enrollment is ongoing. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Ellis:Rafael Pharmaceuticals: Consultancy. Howard:Jazz Pharmaceuticals: Consultancy. Powell:Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. OffLabel Disclosure: Selinexor for the treatment of AML

Correlation Between Bone Marrow Dysplasia and Genomic Profile in De Novo Acute Myeloid Leukemia (AML): A Study By the ALFA Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2568-2568
Author(s):  
Thomas Cluzeau ◽  
Orianne Wagner-Ballon ◽  
Thomas Boyer ◽  
Estelle Guerin ◽  
Emmanuel Benayoun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Cell Lines ◽  
Research Funding ◽  
De Novo ◽  
Normal Karyotype ◽  
The Other ◽  
Molecular Abnormalities ◽  
Other Hand ◽  
De Novo Aml

Abstract Introduction: AML with multilineage dysplasia (MLD) are included in the WHO subset of "AML with myelodysplasia-related changes" (AML-MRC), together with AML arising from previous MDS or AML with MDS-related cytogenetic abnormalities. In the WHO classification, MLD is defined by dysplasia in at least 50% of the cells in at least two bone marrow (BM) myeloid cell lines. On the other hand, some genetically defined AML subgroups are specifically associated with morphologic changes, but close correlations do not exist for most of these entities. We searched for correlations between BM dysplasia and molecular aberrations in de novo AML patients included in 2 ALFA clinical trials Methods: BM cytomorphology was retrospectively reassessed in 192 patients with de novo AML (excluding CBF-AML), aged 18 to 70 enrolled in ALFA-0702 (n=123) and ALFA-0701 (n=69) clinical trials in 5 centers. 4 distinct morphologists performed the analysis from BM smears. Dysmegakaryopoiesis (DM), dyserythropoiesis (DE) and dysgranulopoiesis (DG) were quantified (respectively on 30, 200 and 200 cells) using 22 criteria designed by GFHC, which allow better evaluation of cytoplasmic and nuclear dysplasia in all BM lineages. Dysplasia was also evaluated using WHO criteria. NPM1, FLT3, MLL, CEBPA, IDH1, IDH2, WT1, DNMT3A, RUNX1, TET2 and ASXL1 gene mutations and EVI1 gene overexpression were detected by standard methods, as previously published (Renneville et al. Oncotarget 2014). Results: In the 192 patients analyzed, the incidence of molecular abnormalities was: MLL-PTD 5% (8/155), NPM1 31% (52/170), FLT3-TKD 9% (15/171), FLT3-ITD 19% (34/171), CEBPA double mutated (CEBPA-dm)11% (17/152), EVI1 overexpression 11% (17/152), IDH1 R132 9% (14/146), IDH2 R140 6% (10/159), IDH2 R172 2% (2/92), RUNX1 8% (6/67), DNMT3A 26% (11/43), TET2 12% (5/43) and ASXL1 7% (4/62). DG, DE and DM was evaluable in 59%, 83% and 85% of the patients, respectively. WHO-MLD was identified in 43/192 (22%) patients, and was not significantly associated with any genetic marker, even in AML with normal karyotype (Table 1). On the other hand, when using GFHC criteria, we observed in NPM1 mutated patients a higher % of bi-tri or multi nucleated megakaryocytes (25% vs 10%, p=0.03), of cytoplasmic DG (74% vs 58%, p=0.03); and more dysplasia in other cell lines including eosinophils, basophils, mastocytes, monocytes (p=0.008). In CEBPA-dm patients, lower % of global DG (21% vs 54%, p=0.04) was seen. In EVI1 overexpressing patients, we found a higher % of global DM, of micromegacaryocytes and of hypolobulated megacaryocytes (80% vs 31%, p=0.01; 18% vs 2%, p=0.01 and 19% vs 6%, p=0.001 respectively). In DNMT3A mutated patients, we observed a lower % of bi-tri or multi nucleated megakaryocytes (2% vs 28%, p=0.01) and a higher % of nuclear and cytoplasmic DG (21% vs 2%, p=0.005 and 1.2% vs 0%, p=0.03, respectively). In TET2 mutated patients, we observed less defects in nuclear segmentation and a higher % of abnormal chromatin condensation in granulocytes (1% vs 9%, p=0.02 and 6% vs 0%, p=0.008, respectively). Conclusion: Presence of WHO-MLD was not significantly correlated with any genetic subgroup. The 22 BM dysplasia parameters designed by the GFHC were evaluable in a majority of patients, and allowed us to find some specific cytomorphologic features in de novo AML with NPM1, CEBPA-DM, DNMT3A, TET2 mutation, or EVI1 overexpression. Those findings suggest that the definition of MLD may be refined by using more in depth quantification of dysplasia, especially with GFCH parameters. This study will be expanded with the inclusion of whole exome sequencing data (ongoing). Table 1. Correlation between MLD, normal karyotype and molecular abnormalities % AML-MLD % AML-MLD in AML with normal karyotype MLL-PTD 37,5% 29% NPM1 25% 28% FLT3-TKD 27% 33% FLT3-ITD 27% 25% CEBPA-dm 0% 0% IDH1 R132 21% 18% IDH2 R140 10% 0% IDH2 R172 0% 0% RUNX1 40% 40% DNMT3A 0% 0% TET2 0% 0% ASXL1 25% 50% EVI1 24% 0% Disclosures Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

scholarly journals Selinexor in Combination with Induction and Consolidation Therapy in Older Adults with AML Is Highly Active

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1388-1388
Author(s):  
Timothy S. Pardee ◽  
Kris C Wood ◽  
Kevin H Lin ◽  
Justine Rutter ◽  
Mariaelena Pierobon ◽  
...  
Keyword(s):  
Older Adults ◽  
Nuclear Export ◽  
Research Funding ◽  
De Novo ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Blood Samples ◽  
Highly Active ◽  
De Novo Aml ◽  
Activation Mapping

Background: Acute myeloid leukemia (AML) is an aggressive myeloid cancer of the hematopoietic system that primarily affects older adults and is characterized by therapy resistance and dismal outcomes. Novel approaches to treat AML are desperately needed. Selinexor is a small-molecule inhibitor of the nuclear export protein XPO1. Treatment of AML cells with selinexor was shown to sensitize them to chemotherapy in part by blocking the nuclear export of topoisomerase II, resulting in increased DNA strand breaks when an anthracycline is present. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in the relapsed setting. This abstract reports on the initial results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML 60 years of age or older. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized between 7+3 or 7+3+selinexor induction. Responding patients could then go on to high dose cytarabine consolidation with or without selinexor as per their initial treatment assignment. Patients in the selinexor arm who completed all planned consolidation could then move to maintenance therapy with selinexor alone. During induction cytarabine was dosed at 100 mg/m2 by continuous infusion for 7 days and daunorubicin was dosed at 60 mg/m2 on days 1-3. In consolidation cytarabine was dosed at 1.5 gm/m2 given Q12 hours on days 1, 3 and 5. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days in maintenance. Optional blood samples were collected just prior to and at several time points after selinexor during induction. Mononuclear cells were isolated from these samples, lysed and lysates evaluated for protein pathway drug target activation mapping by reverse phase phosphoprotein array (RPPA). Results: Thirteen patients have been enrolled to date with 12 available for evaluation. Of the 12 evaluable patients 6 were randomized to each arm. Baseline demographics are listed in Table 1. Overall the combination was well tolerated with no patients discontinuing selinexor secondary to treatment related adverse events. In the standard arm 3 of 6 patients achieved a complete remission. Of the 3 responders 1 has relapsed, 1 has gone on to transplant and one has completed consolidation chemotherapy. In the selinexor arm 5 of 6 patients achieved a complete remission and 1 patient achieved a morphologic leukemia free state. All patients given selinexor achieved a response. Of the 5 responders 3 have gone on to transplant, 1 is on maintenance therapy (completed 14 cycles) and one is completing consolidation therapy. In the standard arm no patients died during induction and 3 of 6 patients have died from progressive disease. In the selinexor arm 1 patient died during induction and none of the remaining patients have progressed (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. The patient on long term maintenance selinexor is tolerating it without significant AEs to date. Blood samples were available from 3 patients from the selinexor arm. RPPA based protein pathway activation mapping analysis of PBMCs revealed a significant increase in phosphorylation of AMPK, BAD and LC3B at one-hour post treatment that returned to baseline by 2 hours suggesting a transient increase in these pathways that was subsequently suppressed (Figure 2). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older de novo AML patients. Selinexor may increase response by modulation of AMPK, autophagy and BAD phosphorylation. Enrollment is ongoing. Disclosures Pardee: Spherix Intellectual Property: Research Funding; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics/Janssen: Speakers Bureau; Karyopharm: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding. Manuel:Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Powell:Pfizer: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding. OffLabel Disclosure: Selinexor is not approved for the treatment of AML

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