Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

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Second Malignancies Among Elderly Multiple Myeloma Patients Exposed to Bortezomib and Other Treatments: An Analysis of the US SEER-Medicare Linked Database,

Blood ◽

10.1182/blood.v118.21.3972.3972 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3972-3972

Author(s):

Dina Gifkins ◽

Megan McAuliffe ◽

Amy Matcho ◽

Jane Porter ◽

Scott Chavers ◽

...

Keyword(s):

Multiple Myeloma ◽

Hodgkin Lymphoma ◽

Solid Tumors ◽

Myeloid Leukemia ◽

Lymphocytic Leukemia ◽

Second Malignancy ◽

Second Malignancies ◽

Non Hodgkin Lymphoma ◽

Equity Ownership ◽

Medicare Database

Abstract Abstract 3972 Second hematologic malignancies have been found to occur at a higher rate among multiple myeloma patients compared to the general population. Although alkylating therapy has been suggested to play a role, the underlying causes remain largely unclear. Increased survival benefit has been documented with the introduction of novel agents over the past decade, and, as noted in other cancers, there may also be a higher occurrence of second malignancies in the era of novel therapies. Recently, data from Phase III studies suggest that patients treated with lenalidomide with prior exposure to melphalan may have an increased risk compared to placebo. However, the contribution of other specific agents has not been well characterized. Evaluation of second malignancies in clinical trial and product safety data for bortezomib has not revealed an increased incidence in bortezomib-treated patients. Additionally, our follow-up study of the VISTA clinical trial participants after 5 years showed no elevation in risk (San Miguel, et al. ASH 2011). To expand our current knowledge, we are conducting a population-based study using the NCI SEER-Medicare database (NCI SEER cancer registry linked with diagnostic and treatment claims data of Medicare beneficiaries) to evaluate bortezomib and other standard treatment exposures in relation to second malignancies subsequent to multiple myeloma. Using the NCI SEER-Medicare database, we identified all multiple myeloma patients with their first diagnosis between 1 Jan 2000 and 31 Dec 2007 aged 66 years or older. Exposure to chemotherapy was identified via Medicare claims, and second malignancies, defined as invasive cancers whose onset was after bortezomib-based therapy and occurring at least 2 months after the initial multiple myeloma diagnosis, were identified from the SEER registries. We identified the number of second malignancies among elderly patients with multiple myeloma and following bortezomib exposure; expanded multivariate analyses, adjusted for exposures, will be presented at the meeting. A total of 9,377 multiple myeloma patients were identified (median age 76 years; 50% males). During the study period, 2,285 (21%) patients had any documented exposure to bortezomib (with or without other treatments). Patients with bortezomib exposure had a median age of 73 years, and 55% were male. Among these 2,285 patients with bortezomib exposure, 33 patients (1.4%) developed a second malignancy (4 [0.2%] hematologic and 29 [1.3%] solid tumors) during the study period after their first documented bortezomib exposure. Hematologic tumors were non-Hodgkin lymphoma (n=3) and acute myeloid leukemia (n=1). Solid tumors were prostate (n=4), bladder (n=4), lung and bronchus (n=3), colon (excluding rectum) (n=3), breast (n=3), and other (n=12). Among the 7,092 multiple myeloma patients with no documented exposure to bortezomib, 320 (4.5%) developed a second malignancy (55 [0.8%] hematologic and 265 [3.7%] solid tumors) during the study period. Hematologic tumors were non-Hodgkin lymphoma (n=16), acute myeloid leukemia (n=7), chronic lymphocytic leukemia (n=2), acute lymphocytic leukemia (n=1), chronic myeloid leukemia (n=1), Hodgkin lymphoma (n=1), and other (n=27). Solid tumors were lung and bronchus (n=46), prostate (n=38), colon (excluding rectum) (n=33), melanoma (n=23), bladder (n=21), breast (n=17), and other (n=87). Based on more than 9,000 elderly multiple myeloma patients, we found a lower prevalence of second malignancies among persons exposed to bortezomib compared to those with no documented bortezomib exposure in our unadjusted analysis. To account for survival and adjust for other exposures, expanded analyses will be presented at the meeting, including standardized incidence ratios and calculations of absolute excess risk among patients exposed to bortezomib and other standard treatments compared to the general SEER population, cumulative incidence of second malignancy for each treatment group adjusting for death as a competing risk, and multivariate analyses to assess risk while adjusting for prior and concomitant treatments and other risk factors. Disclosures: Gifkins: Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. McAuliffe:Millennium Pharmaceuticals, Inc.: Employment. Matcho:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Porter:Millennium Pharmaceuticals, Inc.: Employment. Chavers:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Ponsillo:Millennium Pharmaceuticals, Inc.: Employment. King:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Desai:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership.

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Effects of Elotuzumab on Soluble SLAMF7 Levels in Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2964.2964 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2964-2964 ◽

Cited By ~ 3

Author(s):

Jennifer Postelnek ◽

James Sheridan ◽

Steve Keller ◽

Tatiana Pazina ◽

Jennifer Sheng ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Natural Killer Cells ◽

Partial Response ◽

Natural Killer ◽

Disease Burden ◽

Employment Equity ◽

Killer Cells ◽

Equity Ownership ◽

The Mean

Abstract Introduction: Elotuzumab is a humanized monoclonal antibody that binds specifically to Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7; CS1), a glycoprotein highly expressed on the surface of multiple myeloma (MM) cells and on subsets of immune cells, including natural killer cells. SLAMF7 also exists as a soluble form (sSLAMF7) and has been detected in the serum of patients with MM at statistically significant higher levels than healthy individuals. Although the mechanism of action of elotuzumab involves the direct activation of natural killer cells and the initiation of antibody-dependent cell-mediated cytotoxicity of SLAMF7-expressing myeloma cells, its effects on sSLAMF7 have not been reported. The biological significance of sSLAMF7 has not been described in MM; however, it has been suggested that sSLAMF7 may be associated with disease stage. In order to assess the pharmacodynamic and predictive utility of this biomarker, we investigated levels of serum sSLAMF7 at baseline and on treatment (Cycle 2 Day 1 [C2D1]) across several elotuzumab clinical studies (HuLuc63-1703, CA204-009, and CA204-011) in both smoldering MM and relapsed/refractory MM. Additionally, associations between changes in sSLAMF7 and pharmacokinetic parameters were investigated. Lastly, associations between sSLAMF7 and markers of disease burden were also assessed. Methods: Two enzyme-linked immunosorbent assays were developed to detect sSLAMF7 in the presence of elotuzumab: the total assay (TA) detected all forms of sSLAMF7 (both unbound and elotuzumab-bound sSLAMF7) and the free assay (FA) detected only unbound sSLAMF7. Serum was collected from peripheral blood before initiation of treatment (C1D1) and during treatment (C2D1) and assessed for levels of sSLAMF7 by the TA and FA. Soluble component (non-cellular) from bone marrow aspirates were obtained prior to any therapy to assess the relationship between concentrations of sSLAMF7 in matched marrow and blood samples. Results: As previously reported, these data confirm sSLAMF7 expression in patients with MM. The TA demonstrated a significant dose- and time-dependent increase in sSLAMF7 following elotuzumab treatment alone or in combination with either bortezomib/dexamethasone (E-B/d) or lenalidomide/dexamethasone (E-L/d); this increase was not observed in patients treated with bortezomib/dexamethasone (B/d) only. The increase in total sSLAMF7 observed in the TA demonstrated elotuzumab pharmacodynamic specificity and likely reflected stabilization of the protein in the serum. The FA detected a significant decrease in free sSLAMF7 (at C2D1) in both elotuzumab- and non-elotuzumab-treated patients, with the greatest reduction observed in elotuzumab-treated patients. The decrease in free sSLAMF7 detected using the FA, regardless of treatment, suggest the potential use of this biomarker as a surrogate for disease burden. Additionally, the extent of the C2D1 changes in free and total sSLAMF7 following elotuzumab-containing regimens demonstrated a trend for association with increased depth of response (comparing progressive disease/stable disease/minimal response vs partial response vs very good partial response/complete response). Baseline and C2D1 levels of serum sSLAMF7 showed a trend for an inverse relationship with progression-free survival (for E-L/d) but this was not statistically significant. Baseline sSLAMF7 did demonstrate a positive relation with the percentage of bone marrow plasma cells. At C2D1, with the dose of 10 mg/kg, the mean elotuzumab concentration was 337.1 µg/mL (N=38; CV of 51.6%), which was significantly higher than the mean free sSLAMF7 concentration 0.255 ng/mL (N=37; CV of 200%). In addition, E-L/d treatment demonstrated the greatest reduction of free sSLAMF7 (more than 80% of patients treated with E-L/d reached >75% of free sSLAMF7 reduction) compared with that observed for E-B/d and B/d. Conclusions: Together, these data suggest that sSLAMF7 may be a surrogate marker of disease burden in MM, and early changes in sSLAMF7 may provide an indication of likelihood of response. Additional analysis of sSLAMF7 is ongoing and future studies will help us to further understand the use of this biomarker for prognostic or predictive purposes. Study supported by: Bristol-Myers Squibb Disclosures Postelnek: Bristol-Myers Squibb: Employment. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma.. Sheridan:AbbVie Biotherapeutics: Employment, Equity Ownership. Keller:AbbVie Biotherapeutics: Employment, Equity Ownership. Sheng:Bristol-Myers Squibb: Employment, Equity Ownership. Poulart:Bristol-Myers Squibb: Employment. Robbins:Bristol-Myers Squibb: Employment, Other: shareholder.

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Transfusion Requirements and Hospitalization during First Line Treatment Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Were Ineligible for Intensive Chemotherapy

Blood ◽

10.1182/blood-2018-99-117247 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4849-4849

Author(s):

Cat N. Bui ◽

Thomas Marshall ◽

Rajesh Kamalakar ◽

Tracey Posadas ◽

Jalaja Potluri

Keyword(s):

Myeloid Leukemia ◽

Transfusion Requirement ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

First Line ◽

Employment Equity ◽

Transfusion Independence ◽

Transfusion Requirements ◽

Equity Ownership ◽

The Mean

Abstract Background: Newly diagnosed acute myeloid leukemia (ND AML) patients (pts) ineligible for intensive chemotherapy have limited treatment options. Most commonly used low intensity regimens are azacitidine (AZA), decitabine (DEC), or low-dose cytarabine (LDAC). These patients often have low blood counts that may contribute to poor quality of life (QoL) due to high risk for infections and may require transfusion of blood products. The objective of this study was to describe the patient characteristics, treatment patterns, and quantify the clinical outcomes (i.e., transfusion requirements infections and hospitalizations (hosp) among ND AML pts ineligible for intensive chemotherapy who received currently available therapies as first-line (1L) treatment in a real-world cohort. Methods: Eligible pts were found in the de-identified Optum© Clinformatics® Data Mart between 1/1/2010 and 6/30/2017 and had the following: AML at ≥2 encounters (ICD-9/10 codes) at least 30 days apart, ≥ 60 yrs. at diagnosis (dx), and ≥6 months (mo) benefit coverage before and ≥ 3 mo post dx. 1L treatment date (tx-index) was the date of first monotherapy (AZA, DEC, or LDAC) after AML diagnosis. 1L treatment duration was from tx-index to the end of study (EOS) defined as either end of 1L treatment, end of benefit coverage, relapse, or 12/31/2017. Transfusion independence (TI) during 1L treatment was defined as having neither platelets nor red blood cells (RBC) for ≥56 consecutive days (56-day TI). Patients with < 56 days of observation time from tx-index were not classified as achieving ≥56-day TI. During 1L treatment, transfusion support was defined as patients receiving either platelets and/or RBC regardless whether or not patients achieved ≥56-day TI. Sample selection and creation of analytic variables were performed using the Instant Health Data (IHD) platform (BHE, Boston, MA). Statistical analyses were undertaken with SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Among 785 eligible pts, 82.0% had Medicare Advantage, 59.2% were male, and the mean (median; range) age was 74.7 (75.0; range 60.0-89.0) yrs. The mean (median; range) baseline comorbidity score (measured by Quan Charlson Comorbidity Index, CCI) was 1.5 (1.0; 0-11), with an available follow-up period of 13.6 (10.6; 3.0-88.5) mo. As1L treatment, majority of pts received AZA (n=422, 53.8%) followed by DEC (n=337, 43.0%) and LDAC (n=26, 3.3%) and the mean (median; range) duration of treatment was 5.6 (3.7; 0.03-52.0) mo. A total of 4.5% (35) patients had major or minor GI hemorrhage, 1.9% (15) brain hemorrhage, and 48.7% (382) had infections of all grades (AZA: 202/422, 47.9%; DEC: 170/337, 50.5%; LDAC: 10/26, 38.5%). Prior to receiving 1L treatment, 48.0% (377/785) of patients required transfusion of either platelets and/or RBC (Table 1). During 1L treatment, 73.3% (575) of pts received transfusion support with a mean (median; range) of 8.5 (5.0; 1-181) transfusions of either platelets and/or RBC. Among 377 patients with transfusion support prior to 1L treatment, 33.7% (127/377) of patients achieved ≥ 56-day TI during 1L treatment (Table 1). Multivariate logistic regression showed pts with baseline transfusion requirement were less likely to achieve ≥56 consecutive day TI during 1L treatment vs. pts without baseline transfusion requirements (33.7% vs. 58.6%; OR = 0.37; 95% CI = 0.27 - 0.50; P < 0.001) with the current treatments. Among 785 patients during 1L treatment, the mean (median; range) number of hospitalizations was 0.91 (1.0; 0-8). A total of 53.1% (417) had ≥ 1 hospitalization; the mean (median; range) length of an inpatient stay was 10.9 (7.0; 1-97) days for these patients; and 49.4% (206), 75.1% (313), and 87.3% (364) of patients were admitted within 30, 60, 90 days of tx-index, respectively. Conclusions: This real-world study in ND AML patients showed transfusion burden on patients with the currently available non-intensive treatment with AZA and DEC being the most commonly used agents. Most (61.5%-80.1%) of the pts required transfusions for platelets and /or RBC and less than 40% (0%-38.6%) of the patients with baseline transfusion requirement achieved ≥56 consecutive days of transfusion independence anytime while receiving their 1L treatment. Additional research is warranted to understand the correlation between response to treatment and transfusion independence and subsequent impact on hospitalization and infections. Disclosures Bui: AbbVie: Employment. Marshall:AbbVie: Employment, Equity Ownership. Kamalakar:AbbVie: Employment. Posadas:AbbVie: Employment. Potluri:AbbVie: Employment, Equity Ownership.

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Ex Vivo Activity of Immunotherapeutic Approaches Targeting CD38 Against Daratumumab-Resistant Multiple Myeloma Patient Samples

Blood ◽

10.1182/blood-2019-127893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1848-1848

Author(s):

Maria Karvouni ◽

Heyue Zhou ◽

Arnika Kathleen Wagner ◽

Qiangzhong Ma ◽

Alamdar H. Baloch ◽

...

Keyword(s):

Multiple Myeloma ◽

Nk Cells ◽

Therapeutic Potential ◽

Ex Vivo ◽

Phase 1 ◽

Employment Equity ◽

Multiple Myeloma Patient ◽

Myeloma Cells ◽

Car T ◽

Equity Ownership

Background: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. The identification of CD38, a transmembrane glycoprotein overexpressed on MM cells, led to the development of target-specific therapeutics such as the FDA approved monoclonal antibody (mAb) Daratumumab (DARA). Although a valuable treatment option for refractory/relapsed (R/R) MM patients, DARA has a limited response rate of below 50%, which highlights the clinical need for novel therapeutics. Aims: Aiming to further exploit the therapeutic potential of CD38 in the MM setting, immunotherapies based on the novel anti-CD38 mAb CD38A2 were tested. Methods: For the first approach, the CD38A2 mAb -that binds to a unique, distinct from DARA's, CD38 epitope- was conjugated with either the alkylating agent Duomycin (ADC-136) or the microtubulin binder Duostatin (ADC-129). The ADCs were compared to DARA, in cultures of primary MM cells from patients refractory to DARA treatment. In a second approach, a chimeric antigen receptor (CAR) consisting of the CD38A2 scFv and the intracellular domains of CD28 and CD3ζ was used to transduce primary T and NK cells from R/R MM patients. The functionality of the CAR-T and CAR-NK cells was assessed in cytotoxicity assays against autologous myeloma cells. Results: ADC-136 demonstrated the most potent cytotoxicity against the MM cells with an IC50 of 6pM at day 6 following a single dose treatment. ADC-129 showed cell killing with an IC50 of 30pM, while DARA did not exhibit appreciable cytotoxicity. Regarding the cell therapy approach, patients' T and NK cells were effectively transduced, showing a CD38A2-CAR expression ranging between 11-68%. In functional assays, CAR-T and CAR-NK cells were assayed against autologous myeloma cells, where they exhibited an increase in target cell cytotoxicity, compared to the untransduced cells. Summary/Conclusion: Altogether, our preliminary findings demonstrate that CD38 targeting using CD38A2-based immunotherapies could be a viable therapeutic approach in R/R MM patients previously exposed to DARA. Currently, an anti-CD38 CAR-T therapy based on CD38A2 is being evaluated in Phase 1 studies in R/R MM patients by Sorrento Therapeutics, Inc. Disclosures Zhou: Sorrento Therapeutics Inc: Employment, Equity Ownership. Ma:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhu:Sorrento Therapeutics Inc: Employment, Equity Ownership. Zhang:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

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p53 Mediated Bone Marrow Mesenchymal Stem Cell Expansion Supports Acute Myeloid Leukemia Development

Blood ◽

10.1182/blood-2019-127245 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 523-523

Author(s):

Rasoul Pourebrahimabadi ◽

Zoe Alaniz ◽

Lauren B Ostermann ◽

Hung Alex Luong ◽

Rafael Heinz Montoya ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Osteoblast Differentiation ◽

Hematopoietic Cells ◽

Advisory Committees ◽

Equity Ownership ◽

Mdm2 Inhibitor ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease that develops within a complex microenvironment. Reciprocal interactions between the bone marrow mesenchymal stem/stromal cells (BM-MSCs) and AML cells can promote AML progression and resistance to chemotherapy (Jacamo et al., 2014). We have recently reported that BM-MSCs derived from AML patients (n=103) highly express p53 and p21 compared to their normal counterparts (n=73 p<0.0001) (Hematologica, 2018). To assess the function of p53 in BM-MSCs, we generated traceable lineage specific mouse models targeting Mdm2 or Trp53 alleles in MSCs (Osx-Cre;mTmG;p53fl/fl and Osx-Cre;mTmG;Mdm2fl/+) or hematopoietic cells (Vav-Cre;mTmG;p53fl/fl and Vav-Cre;mTmG;Mdm2fl/+). Homozygote deletion of Mdm2 (Osx-Cre;Mdm2fl/fl) resulted in death at birth and displayed skeletal defects as well as lack of intramedullary hematopoiesis. Heterozygote deletion of Mdm2 in MSCs was dispensable for normal hematopoiesis in adult mice, however, resulted in bone marrow failure and thrombocytopenia after irradiation. Homozygote deletion of Mdm2 in hematopoietic cells (Vav-Cre;Mdm2fl/fl) was embryonically lethal but the heterozygotes were radiosensitive. We next sought to examine if p53 levels in BM-MSCs change after cellular stress imposed by AML. We generated a traceable syngeneic AML model using AML-ETO leukemia cells transplanted into Osx-Cre;mTmG mice. We found that p53 was highly induced in BM-MSCs of AML mice, further confirming our findings in primary patient samples. The population of BM-MSCs was significantly increased in bone marrow Osx-Cre;mTmG transplanted with syngeneic AML cells. Tunnel staining of bone marrow samples in this traceable syngeneic AML model showed a block in apoptosis of BM-MSCs suggesting that the expansion of BM-MSCs in AML is partly due to inhibition of apoptosis. As the leukemia progressed the number of Td-Tomato positive cells which represents hematopoietic lineage and endothelial cells were significantly decreased indicating failure of normal hematopoiesis induced by leukemia. SA-β-gal activity was significantly induced in osteoblasts derived from leukemia mice in comparison to normal mice further supporting our observation in human leukemia samples that AML induces senescence of BM-MSCs. To examine the effect of p53 on the senescence associated secretory profile (SASP) of BM-MSCs, we measured fifteen SASP cytokines by qPCR and found significant decrease in Ccl4, Cxcl12, S100a8, Il6 and Il1b upon p53 deletion in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) compared to p53 wildtype mice. To functionally evaluate the effects of p53 in BM-MSCs on AML, we deleted p53 in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) and transplanted them with syngeneic AML-ETO-Turquoise AML cells. Deletion of p53 in BM-MSCs strongly inhibited the expansion of BM-MSCs in AML and resulted in osteoblast differentiation. This suggests that expansion of BM-MSCs in AML is dependent on p53 and that deletion of p53 results in osteoblast differentiation of BM-MSCs. Importantly, deletion of p53 in BM-MSCs significantly increased the survival of AML mice. We further evaluated the effect of a Mdm2 inhibitor, DS-5272, on BM-MSCs in our traceable mouse models. DS-5272 treatment of Osx-cre;Mdm2fl/+ mice resulted in complete loss of normal hematopoietic cells indicating a non-cell autonomous regulation of apoptosis of hematopoietic cells mediated by p53 in BM-MSCs. Loss of p53 in BM-MSCs (Osx-Cre;p53fl/fl) completely rescued hematopoietic failure following Mdm2 inhibitor treatment. In conclusion, we identified p53 activation as a novel mechanism by which BM-MSCs regulate proliferation and apoptosis of hematopoietic cells. This knowledge highlights a new mechanism of hematopoietic failure after AML therapy and informs new therapeutic strategies to eliminate AML. Disclosures Khoury: Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding. Bueso-Ramos:Incyte: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Mdm2 inhibitor-DS 5272

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Highly Differentiated Anti-CD47 Antibody, AO-176, Potently Inhibits Hematologic Malignancies Alone and in Combination

Blood ◽

10.1182/blood-2019-126298 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1844-1844

Author(s):

John Richards ◽

Myriam N Bouchlaka ◽

Robyn J Puro ◽

Ben J Capoccia ◽

Ronald R Hiebsch ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Tumor Growth ◽

Growth Inhibition ◽

Tumor Cells ◽

Tumor Growth Inhibition ◽

Employment Equity ◽

Equity Ownership

AO-176 is a highly differentiated, humanized anti-CD47 IgG2 antibody that is unique among agents in this class of checkpoint inhibitors. AO-176 works by blocking the "don't eat me" signal, the standard mechanism of anti-CD47 antibodies, but also by directly killing tumor cells. Importantly, AO-176 binds preferentially to tumor cells, compared to normal cells, and binds even more potently to tumors in their acidic microenvironment (low pH). Hematological neoplasms are the fourth most frequently diagnosed cancers in both men and women and account for approximately 10% of all cancers. Here we describe AO-176, a highly differentiated anti-CD47 antibody that potently targets hematologic cancers in vitro and in vivo. As a single agent, AO-176 not only promotes phagocytosis (15-45%, EC50 = 0.33-4.1 µg/ml) of hematologic tumor cell lines (acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, and T cell leukemia) but also directly targets and kills tumor cells (18-46% Annexin V positivity, EC50 = 0.63-10 µg/ml) in a non-ADCC manner. In combination with agents targeting CD20 (rituximab) or CD38 (daratumumab), AO-176 mediates enhanced phagocytosis of lymphoma and multiple myeloma cell lines, respectively. In vivo, AO-176 mediates potent monotherapy tumor growth inhibition of hematologic tumors including Raji B cell lymphoma and RPMI-8226 multiple myeloma xenograft models in a dose-dependent manner. Concomitant with tumor growth inhibition, immune cell infiltrates were observed with elevated numbers of macrophage and dendritic cells, along with increased pro-inflammatory cytokine levels in AO-176 treated animals. When combined with bortezomib, AO-176 was able to elicit complete tumor regression (100% CR in 10/10 animals treated with either 10 or 25 mg/kg AO-176 + 1 mg/kg bortezomib) with no detectable tumor out to 100 days at study termination. Overall survival was also greatly improved following combination therapy compared to animals treated with bortezomib or AO-176 alone. These data show that AO-176 exhibits promising monotherapy and combination therapy activity, both in vitro and in vivo, against hematologic cancers. These findings also add to the previously reported anti-tumor efficacy exhibited by AO-176 in solid tumor xenografts representing ovarian, gastric and breast cancer. With AO-176's highly differentiated MOA and binding characteristics, it may have the potential to improve upon the safety and efficacy profiles relative to other agents in this class. AO-176 is currently being evaluated in a Phase 1 clinical trial (NCT03834948) for the treatment of patients with select solid tumors. Disclosures Richards: Arch Oncology Inc.: Employment, Equity Ownership, Other: Salary. Bouchlaka:Arch Oncology Inc.: Consultancy, Equity Ownership. Puro:Arch Oncology Inc.: Employment, Equity Ownership. Capoccia:Arch Oncology Inc.: Employment, Equity Ownership. Hiebsch:Arch Oncology Inc.: Employment, Equity Ownership. Donio:Arch Oncology Inc.: Employment, Equity Ownership. Wilson:Arch Oncology Inc.: Employment, Equity Ownership. Chakraborty:Arch Oncology Inc.: Employment, Equity Ownership. Sung:Arch Oncology Inc.: Employment, Equity Ownership. Pereira:Arch Oncology Inc.: Employment, Equity Ownership.

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

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

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

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Relationship Between Cleaved L-Selectin Levels and the Outcome of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v92.9.3115 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3115-3122 ◽

Cited By ~ 9

Author(s):

M. Extermann ◽

M. Bacchi ◽

N. Monai ◽

M. Fopp ◽

M. Fey ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

High Plasma ◽

Multivariate Statistical ◽

Free Survival ◽

The Mean ◽

American Society ◽

The Relationship ◽

Acute Myeloid

Abstract High plasma levels of the shed form of L-selectin (sL-selectin) are frequently detectable in acute myeloid leukemia (AML). sL-selectin can inhibit blast cell adhesion to vascular endothelium and may thereby influence the phenotype of AML. In this study, we have investigated the relationship between sL-selectin levels and clinical presentation or disease outcome in 100 patients with AML. Fifty-eight patients were found to have sL-selectin levels ≥3.12 μg/mL (≥3 SD above the mean of healthy controls: “increased”). Patients with extramedullary disease such as lymphadenopathies, splenomegaly, hepatomegaly, and/or muco-cutaneous infiltration had significantly increased sL-selectin levels (P < .001). sL-selectin levels were significantly heterogeneous in the French-American-British subtypes (P = .0003). Patients with “normal” sL-selectin levels had higher probability of achieving complete remission (CR) than with “increased” levels: 81% versus 64%, respectively (P = .06). When adjusting for clinically relevant covariates predictive for CR (sex, age, Auer rods), “normal” sL-selectin levels were significantly associated with CR (odds ratio, 3.08; 95% confidence interval [CI], 1.10 to 8.58;P = .03). Moreover, patients with “increased” sL-selectin levels (≥3.12 μg/mL) had shorter event-free survival (EFS) (median 7.3 v 12 months, P = .008) and overall survival (median 1 v 2.05 years, P = .03) than patients with sL-selectin <3.12 μg/mL. Multivariate statistical analysis (adjusted for age and presence of Auer rods) indicated that sL-selectin was an independent prognostic factor for EFS (hazard ratio [HR], 1.96; 95% CI, 1.21 to 3.17, P = .006) and overall survival (HR, 1.80; 95% CI, 1.09 to 2.98; P = .02). Thus, plasma sL-selectin may be a useful prognostic marker in the evaluation of AML at diagnosis. © 1998 by The American Society of Hematology.

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Myeloma Proteins, Bence Jones Proteins and Normal Immunoglobulins in Multiple Myeloma

Blood ◽

10.1182/blood.v30.3.265.265 ◽

1967 ◽

Vol 30 (3) ◽

pp. 265-287 ◽

Cited By ~ 20

Author(s):

VINCENT CAGGIANO ◽

JANET CUTTNER ◽

ALAN SOLOMON

Keyword(s):

Multiple Myeloma ◽

Response To Therapy ◽

Treatment Schedule ◽

Myeloma Protein ◽

Mean Values ◽

Multiple Components ◽

The Mean ◽

Therapeutic Protocols ◽

The Relationship ◽

Chain Type

Abstract The relationship between the anomalous and normal immunoglobulins was studied through measurement of myeloma protein (MP), Bence Jones protein (BJP), and the normal γG, γA, γM and γD-globulin levels in a large group of patients with multiple myeloma. These determinations were made prior to and after initiation of three different therapeutic protocols. Thirteen out of 18 patients had at least a 25 per cent reduction in MP or BJP within 6 months. This response was characterized by considerable variation both in the rate and period of time before the anomalous proteins decreased. The type of response was independent of (1) light chain type (K or L) of G or A-MP, (2) heavy chain subgroup or genetic (Gm) factors of G-MP, and (3) electrophorectic mobility of the MP. The ratio among multiple components of heterogenous G or A-MP was not altered by therapy. The initial level of MP, in the case of patients with G-MP, may be one factor in the type of response observed. The rate of reduction of MP and BJP was extremely rapid in patients who received prednisone in conjunction with melphalan. It appeared that synthesis of anomalous γ-globulin components was completely suppressed with this treatment regimen. This type of response was not observed in patients treated with melphalan alone. The mean values for each of the normal immunoglobulin (IG) classes (γG, γA, γM and γD-globulin) were reduced below normal. Two classes, γA and γD-globulin, were particularly low. Prior to therapy, however, the extent of reduction of each IG class varied in an individual patient. An inverse relationship was found for γM-globulin and G-MP levels. Part of the normal γG-globulin in patients with G-MP was determined by measurement of Vi (γ2c) levels. Different patterns of response to therapy were noted for each class of IG. More commonly, the response of a normal IG was independent of the response of the anomalous protein and furthermore, could not be related to a particular treatment schedule. In some instances, therapy contributed to further suppression of normal IG levels.

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Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Blood ◽

10.1182/blood.v114.22.2213.2213 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2213-2213

Author(s):

Richard A. Larson ◽

Yen Lin Chia ◽

Camille Granvil ◽

François Guilhot ◽

Brian J. Druker ◽

...

Keyword(s):

Steady State ◽

Clinical Response ◽

Cumulative Dose ◽

Research Funding ◽

Risk Scores ◽

Employment Equity ◽

Risk Patients ◽

Equity Ownership ◽

Grade 3 ◽

Trough Levels

Abstract Abstract 2213 Poster Board II-190 Background: Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods: Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results: Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. Conclusion: IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

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