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

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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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

Blood ◽

10.1182/blood-2019-131481 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5768-5768

Author(s):

Adekemi Taylor ◽

Martine Allard ◽

Cecile Kresja ◽

Dana Lee ◽

Greg Slatter

Keyword(s):

Multiple Myeloma ◽

Steady State ◽

Solid Tumors ◽

Upper Bound ◽

Myeloid Leukemia ◽

Employment Equity ◽

Equity Ownership ◽

The Mean ◽

The Relationship ◽

Mdm2 Inhibitor

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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Efficacy and Tolerability of Bosutinib and Imatinib in Older Versus Younger Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia–BELA Trial

Blood ◽

10.1182/blood.v120.21.4442.4442 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4442-4442 ◽

Cited By ~ 3

Author(s):

Carlo Gambacorti-Passerini ◽

Tim H Brümmendorf ◽

Dong-Wook Kim ◽

Irina Dyagil ◽

Hagop M Kantarjian ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Kaplan Meier ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4442 Bosutinib (BOS) is an orally active, dual Src/Abl kinase inhibitor with activity and manageable toxicity in the phase 3 BELA trial of patients (pts) with newly diagnosed (≤6 mo) chronic phase (CP) chronic myeloid leukemia (CML). The current analysis of the BELA trial summarizes the activity and tolerability of BOS 500 mg/d and imatinib (IM) 400 mg/d among older (≥65 y; BOS n = 30; IM n = 27) versus younger pts (<65 y; BOS n = 220; IM n = 225). Sokal risk scores were balanced between treatment arms but, as expected, higher among older pts (4% low; 72% intermediate; 25% high) versus younger pts (39% low; 44% intermediate; 17% high). Minimum follow-up duration was 24 mo. BOS was discontinued by 37% of pts (57% older vs 35% younger; P = 0.023); difference between age groups was primarily due to adverse events (AEs; 39% vs 22%; most commonly increased alanine aminotransferase [ALT]). IM was discontinued by 27% of pts (35% older vs 28% younger; P= 0.496); disease progression was the primary reason. In the intent-to-treat population, cumulative rate of complete cytogenetic response (CCyR) by 24 mo in older/younger pts was 70%/80% on BOS and 78%/80% on IM. Median time to CCyR was 24.0 wk for older versus 12.7 wk for younger pts on BOS and 24.4 wk versus 24.7 wk on IM; in younger pts CCyR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a CCyR, 57%/79% on BOS and 76%/85% on IM were still on treatment and retained their CCyR as of the data cutoff. Cumulative rates of major molecular response (MMR) by 24 mo in older/younger pts were 53%/60% on BOS and 48%/49% on IM. Median time to MMR was 48.1 wk for older versus 48.0 wk for younger pts on BOS and 60.6 wk versus 84.1 wks on IM; for younger pts MMR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a MMR, 63%/84% on BOS and 92%/89% on IM were still on treatment and retained their MMR as of the data cutoff. Kaplan-Meier event-free survival in older/younger pts at 2 y was 100%/91% on BOS and 81%/88% on IM. Kaplan-Meier on-treatment transformation to accelerated/blast phase CML by 2 y was 0% for older and 2% (4 transformations) for younger pts on BOS (4 total), and 9% (2 transformations) for older and 5% (11 transformations) for younger pts on IM (13 total). Kaplan-Meier overall survival in older/younger pts at 2 y was 100%/97% on BOS and 92%/95% on IM. The majority of deaths were due to disease progression (BOS, n = 6; IM, n = 10); few deaths due to AEs on BOS (n = 1) or IM (n = 2) were reported, none treatment related. BOS was associated with higher rates of gastrointestinal TEAEs, elevated ALT and aspartate aminotransferase (AST), and pyrexia; IM was associated with higher rates of musculoskeletal TEAEs and edema (Table). Rates of common TEAEs were generally similar or higher among older pts. Pleural/pericardial effusion occurred in 6 (21%) older pts (3/6 with treatment-related events; median event duration, 36.5 d) versus 5 (2%) younger pts (all with treatment-related events) on BOS, and in no IM pts. Overall grade 3/4 TEAEs were more frequent among older pts on both BOS and IM, as was dose modification (Table). Grade 3/4 lab abnormalities of elevated ALT (BOS, 18% older/24% younger; IM, 4% each) and AST (BOS, 7%/12%; IM, 4% each) were more frequent with BOS versus IM, but similar between age groups. Grade 3/4 lab abnormalities of neutropenia were more frequent with IM (23% older/22% younger) versus BOS (11% each) regardless of age; grade 3/4 anemia (6%-14%) and thrombocytopenia (14%-23%) were generally similar regardless of age or treatment arm. In conclusion, BOS demonstrated activity in both older and younger pts with newly diagnosed CP CML. Although the frequency of certain toxicities as well as treatment discontinuations due to TEAEs was higher among older pts, the toxicity profile of BOS remained manageable and distinct from that of IM regardless of age. Event, % BOS IM ≥65 y (n = 28) <65 y (n = 220) ≥65 y (n = 26) <65 y (n = 225) Non-hematologic TEAEsa Diarrhea 86 68 46 22 Rash 36 22 27 18 Nausea 36 32 31 37 Vomiting 32 32 19 15 Dyspnea 32 5 12 3 Pyrexia 29 17 4 13 Elevated ALT 29 32 15 8 Elevated AST 25 27 15 8 Elevated lipase 25 12 19 10 Headache 21 12 8 12 Asthenia 21 5 4 7 Dyspepsia 14 6 23 5 Muscle spasms 14 3 35 21 Periorbital edema 7 <1 35 12 Any grade 3/4 TEAE 89 65 73 56 Dose reduction due to AE 64 40 42 18 Dose interruption due to AE 89 63 69 42 Treatment discontinuation due to AE 39 22 8 9 All treated pts were included in the safety analyses. a Includes TEAEs reported for ≥20% of older or younger pts. Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

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Assessment Of Human Equilibrative Nucleoside Transporter 1 (hENT1) – Expression By Flow Cytometry In Acute Myeloid Leukemia and Myelodysplastic Syndromes and Correlation To Clinical Outcome In Acute Myeloid Leukemia Patients Treated With Intensive Chemotherapy

Blood ◽

10.1182/blood.v122.21.2582.2582 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2582-2582 ◽

Cited By ~ 1

Author(s):

Frauke Bellos ◽

Bruce H. Davis ◽

Naomi B. Culp ◽

Birgitte Booij ◽

Susanne Schnittger ◽

...

Keyword(s):

Flow Cytometry ◽

Myeloid Leukemia ◽

De Novo ◽

Molecular Genetic ◽

Newly Diagnosed ◽

Employment Equity ◽

Equity Ownership ◽

De Novo Aml ◽

Very High ◽

Acute Myeloid

Abstract Background Nucleoside analogs depend on cellular hENT1 expression for entry into cells and cytotoxic activity. Studies suggest low cellular hENT1 levels correlate with poor response to such chemotherapies in solid tumors, data on AML and MDS is scarce. Aim To examine hENT1 expression by multiparameter flow cytometry (MFC) in newly diagnosed AML and MDS and correlate results to morphologic, cytogenetic (CG) and molecular genetic (MG) findings. To examine hENT1 expression with respect to clinical outcome in AML patients (pts) treated with intensive cytarabine-based chemotherapy (CHT). Methods We studied pts with newly diagnosed AML (n=145) and MDS (n=96), 133/108 male/female, median age 67.3 (AML) and 73.3 years (MDS). CG was done in 130 AML and 86 MDS. Pts included 107 de novo AML, 9 t-AML, 29 s-AML; FAB: 9 M0, 27 M1, 50 M2, 9 M3, 21 M4, 8 M4eo, 7 M5, 14 not classified; by CG (MRC): 21 favorable, 75 intermediate, 34 adverse. 91 were de novo MDS, 5 t-MDS; 1 RARS, 17 RCMD-RS, 37 RCMD, 3 5q- syndrome, 3 RAEB-1, 5 RAEB-2, 1 CMML, 24 not classified; 2 IPSS-R very low, 55 IPSS-R low, 8 IPSS-R intermediate, 8 IPSS-R high, 13 IPSS-R very high. hENT1 expression was quantified by a novel four color intracellular staining assay using monoclonal antibodies against hENT1, CD45, CD64 and myeloperoxidase. Median fluorescence intensities (MFI) of hENT1 were determined in myeloid progenitors (MP), granulocytes (G) and monocytic cells (Mo) and correlated to hENT1 MFI in lymphocytes to derive hENT1 index (index). Results No correlation of index to age, gender, hemoglobin level or counts for blasts, WBC or platelets was detected. In AML, we generally saw higher index by trend in the more favorable prognostic subgroups. M3/t(15;17)/PML-RARA+ displayed higher index in MP than non-M3 AML (4.24 vs 2.56, p<0.001). G index was lower in M0 (3.01) vs M1, M2, M4 and M4eo (5.66, 4.34, 5.35, 4.77; p=0.01, 0.028, 0.004, 0.043, respectively) and in M2 compared to M1 and M4 (4.34. vs 5.66 and 5.35, p=0.01 and 0.033, respectively). M2 showed lower MP index than M5 (2.42 vs 2.99, p=0.016). Considering CG, index in MP was higher in favorable vs intermediate and adverse pts (3.05 vs 2.58 and 2.53, p=0.034 and 0.023, respectively), Mo index was higher ín favorable vs adverse pts (3.17 vs 2.71, p=0.044). By MG, higher index in Mo and G was observed in RUNX1-RUNX1T1+ AML (4/83, 4.32 vs 3.04, p=0.01; 8.16 vs 4.60, p=0.002, respectively). Higher index for MP was found in FLT3-ITD mutated (mut) (18/111; 3.19 vs 2.62, p=0.012), CEPBA mut (4/26, 3.15 vs 2.35, p=0.004) and for Mo in NPM1 mut AML (23/104; 3.72 vs 2.84, p=0.02), whereas lower index for MP was found in RUNX1mut pts (13/65; 2.17 vs 2.59, p=0.031). De novo AML displayed higher MP index than s-AML (2.7 vs 2.28, p=0.008). Using lowest quartile of index for MP (2.1185) as cut-off, AML pts in the MRC intermediate group treated with CHT (n=38) had inferior OS if MP index was below vs above this cut-off (OS at 6 months 63% vs. 95%, p=0.017, median follow up 4.6 months). MDS showed lower Mo and MP index than AML (2.68 vs 2.96, p=0.021, 1.84 vs 2.65, p<0.001, respectively). By IPSS-R, significance was reached for higher index in Mo and MP in very low risk compared to low risk pts (3.39 vs 2.54, p=0.013 and 4.07 vs 1.78, p<0.001, respectively), MP in very low compared to intermediate and high risk pts (4.07 vs 1.95, p=0.004; 4.07 vs 1.76, p=0.002), and MP and G in very low vs very high risk pts (4.07 vs 1.71, p=0.005; 5.86 vs 3.85, p=0.001, respectively). IPSS-R intermediate vs poor and very poor showed lower G index (5.47 vs 3.59, p=0.018 and vs 3.85, p=0.034 respectively). Conclusion AML with genetic and molecular genetic good risk profile had higher hENT1 expression in MP, G and Mo, suggesting a causal mechanism for better response to CHT and better outcome. Consequently, AML with poor risk molecular genetics (RUNX1 mut) showed lower levels of hENT1 in MP. The detection of higher levels in FLT3-ITD mut pts is in line with reportedly good response to CHT, overall worse outcome being mostly due to early relapses. Strikingly, we saw differences in outcome in pts treated with CHT according to hENT1 expression with shorter OS in pts with low index for MP. Higher index in de novo AML than s-AML and MDS may be causal for better response to nucleoside-based CHT in de novo AML. Data for MDS may be interpreted accordingly, lower risk cases showing higher index in MP, G and Mo. Further analyses are needed to explore hENT1 expression in AML and MDS more comprehensively. Disclosures: Bellos: MLL Munich Leukemia Laboratory: Employment. Davis:Trillium Diagnostics, LLC: Equity Ownership. Culp:Trillium Diagnostics, LLC: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

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

Blood ◽

10.1182/blood.v130.suppl_1.890.890 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 890-890

Author(s):

Andrew Wei ◽

Stephen A. Strickland ◽

Gail J. Roboz ◽

Jing-Zhou Hou ◽

Walter Fiedler ◽

...

Keyword(s):

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

Intensive Chemotherapy ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Low Dose Cytarabine

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

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Open-Label, Phase 2 Study of Blinatumomab after First-Line Rituximab-Chemotherapy in Adults with Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-121708 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4077-4077 ◽

Cited By ~ 5

Author(s):

Deborah A. Katz ◽

Michael P. Chu ◽

Kevin A. David ◽

Catherine Thieblemont ◽

Nicholas J. Morley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Metabolic Response ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.

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Quality-Adjusted Survival for Low-Dose Cytarabine (LDAC) Versus Glasdegib+LDAC Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Not Candidates for Intensive Chemotherapy: A Q-TWiST Analysis

Blood ◽

10.1182/blood-2019-126672 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2610-2610 ◽

Cited By ~ 1

Author(s):

Youngmin Kwon ◽

Timothy J Bell ◽

Caitlyn Solem ◽

Joseph C Cappelleri ◽

Courtney Johnson ◽

...

Keyword(s):

Adverse Events ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Equity Ownership ◽

Relative Gains ◽

Mean Time ◽

Low Dose Cytarabine

Introduction: The efficacy and safety of glasdegib (a selective oral inhibitor of hedgehog signaling pathway) in combination with low-dose cytarabine (LDAC) was evaluated in a randomized, phase 2 trial of newly diagnosed acute myeloid leukemia (AML) patients (BRIGHT AML 1003; NCT01546038). Patients receiving glasdegib+LDAC experienced statistically significant and meaningful gains in overall survival (OS) compared with patients receiving LDAC alone (median OS [95% CI]): 8.3 months [4.7-12.2] vs 4.3 months [1.9-5.7]). This analysis examined whether quality-adjusted survival improvements were similarly observed using a quality-adjusted time without symptoms of disease progression or toxicities (Q-TWiST) approach to evaluate possible trade-offs between time with adverse events (toxicities), time in relapse/progression (i.e., with symptoms of disease), and 'good' survival (i.e., time without toxicities or symptoms of progression [TWiST]) when comparing regimens. Methods: OS in BRIGHT AML 1003 data, restricted to a follow-up of 20 months, was partitioned into time with toxicity (TOX: grade 3+ adverse events prior to progression), TWiST, and time post-progression (REL). Progression was defined as treatment discontinuation due to insufficient clinical response or death; patients who discontinued for other reasons (including adverse events) were censored at the date of discontinuation unless death occurred within 28 days of discontinuation. Q-TWiST was calculated by multiplying restricted mean time in each state by respective utilities (U) and then summing up the utility-adjusted time. Base case analysis used U(TOX)=U(REL)=0.5 and U(TWiST)=1.0; threshold analyses were performed varying U(TOX) and U(REL) jointly each from 0 to 1. Relative gains in Q-TWiST (i.e., Q-TWiST difference (combination vs LDAC) / OS in LDAC arm) of ≥15% were considered clearly clinically meaningful per the clinical literature. Sensitivity analysis varied the length of follow-up and AE definitions; subgroup analyses were also performed. 95% confidence intervals were obtained using the bootstrap procedure. Results: At 20 months of follow-up, the survival rate for glasdegib+LDAC and LDAC arm was 28.2% and 7.9%, respectively. Glasdegib+LDAC patients (n=78) compared with LDAC patients (n=38) had significantly longer mean time in TWiST (+3.4 [95% confidence interval: 1.8, 5.2] months) and TOX (+0.8 [0.1, 1.6] months), and longer but non-significant REL (+0.3 [-1.9, 2.3] months). Q-TWiST was 4.0 [2.1, 5.8] months longer for glasdegib+LDAC, translating into a 75% relative improvement in quality-adjusted survival relative to LDAC alone. In threshold analyses, absolute and relative Q-TWiST gains ranged from 3.5 to 4.5 months and 66% to 85%, respectively (Table 1). They exceeded the clinically meaningful threshold for gains in Q-TWiST and were statistically significant across all combinations of U(TOX) and U(REL). Results were robust to length of follow-up 6 to 24 month and remained significant when including all adverse events regardless of grade. Discussions/Conclusions: Glasdegib+LDAC is an add-on therapy that has demonstrated significant survival benefits for newly diagnosed AML patients who are unable to receive intensive chemotherapy. While patients can experience a longer time with toxicities from receiving glasdegib+LDAC (as expected since it is given as an add-on therapy), the trade-off can still be favorable as the treatment provides added time spent in 'good' health (i.e., a significantly longer time in TWiST). In the BRIGHT AML 1003 cohort, the relative gains in OS greatly exceeded previously established thresholds for being clearly clinically meaningful, which suggests that the benefits of glasdegib+LDAC vs LDAC alone outweigh the risks. Table 1 Disclosures Kwon: Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Solem:Pharmerit International: Employment; Pfizer Inc.: Research Funding. Cappelleri:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Hoang:Pfizer Inc.: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

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Single Cell Network Profiling (SCNP) Signatures Predict Response to Induction Therapy and Relapse Risk In Pediatric Patients with Acute Myeloid Leukemia: Children's Oncology Group (COG) Study POG-9421

Blood ◽

10.1182/blood.v116.21.954.954 ◽

2010 ◽

Vol 116 (21) ◽

pp. 954-954

Author(s):

Norman J. Lacayo ◽

Aileen Cohen ◽

Matt Westfall ◽

Alan Lackey ◽

Xiaohua (Robert) Xin ◽

...

Keyword(s):

Dna Damage ◽

Acute Myeloid Leukemia ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Univariate Analysis ◽

Newly Diagnosed ◽

Employment Equity ◽

Equity Ownership ◽

Acute Myeloid

Abstract Abstract 954 Background: About 90% of pediatric patients with newly diagnosed acute myeloid leukemia (AML) have disease responsive to chemotherapy and achieve an initial complete response (CR) with anthracycline/cytarabine-based induction chemotherapy. However, 30–70% of patients of varying risks relapse within 4–5 years. Prospective identification of patients unlikely to benefit from induction therapy or likely to relapse could spare patients from treatment-related toxicities and allow consideration of alternative therapies. Current prognostic factors (e.g., cytogenetics and FLT3 ITD) of value at the population level are imperfect at the individual level. SCNP is a tool used to measure the effects of multiple modulators (including drugs) on signaling pathways at both the single-cell and individual patient level. A set of classifiers has been developed using SCNP technology that predicts the likelihood of response to anthracycline/cytarabine-based induction in adult patients with newly diagnosed AML. This training set has led to the development of classifiers that predict the response to anthracycline/cytarabine-based induction therapy and risk of disease relapse for pediatric patients with newly diagnosed AML. Validation in additional COG cohorts will lead to a novel SCNP classifier that can be used in the clinic. Methods: SCNP assays were performed on 77 bone marrow samples from pediatric AML patients enrolled in POG trial 9421 of which 67 were evaluable/had sufficient data for analysis and were enriched for non-responders (NR). 80 combinations of modulators and intra-cellular proteins (signaling nodes) were investigated including nodes involved in the phosphoinositide 3-kinase (PI3K), Janus Kinases (JAK), signal transducers and activators of transcription (STAT) and the DNA damage response and apoptosis pathways. Basal and modulated protein levels in leukemic blasts were measured using several metrics (e.g., fold change, total level of phosphorylation, and a rank based method Uu measuring the proportion of cells that shift from baseline), and nodes were examined in univariate and multivariate analyses for their ability to discriminate between responders (CR, n=46) and non-responders (NR, n=21) to anthracycline/cytarabine-based induction therapy. Furthermore, nodes were examined for their ability to identify patients likely to be in complete continuous remission (CCR, n=23) or relapse (CR-Rel, n=23) within 4 years. Results: Univariate analysis revealed 19 nodes associated with disease response to conventional induction therapy and 9 associated with CR-Rel (i.e., area under the operator/receiver curve (AUC of ROC=AUC*) >0.65; p<0.05). As in adult studies, nodes involved in the apoptotic response to agents inducing DNA damage (e.g., etoposide→c-PARP AUC* 0.83, AraC+Daunorubicin→c-PARP AUC* 0.76, AraC+Daunorubicin→p-Chk2 AUC* 0.71) showed higher levels of apoptosis in CR samples than in NR samples. Similarly, FLT3 and SCF phosphorylation levels of PI3K pathway members S6 (AUC* 0.70) and ERK (AUC* 0.65) were also higher in CR samples, while hydrogen peroxide as a modulator (acting either as a reactive oxygen species or as a phosphatase inhibitor) revealed lower p-Akt and p-PLC γ levels in NR samples (AUC* 0.70 for both). In multivariate analysis combination of 2–8 nodes (representing apoptosis, Jak/Stat and PI3K pathways) resulted in classifiers with good performance characteristics (bootstrap adjusted AUC* 0.84 – 0.88) in predicting response to induction therapy. Increased sensitivity to etoposide and anthracycline/cytarabine was also associated with CCR in univariate analysis (AUC* 0.77 and 0.68 respectively). Thapsigargin, a modulator known to raise intracellular calcium, induced p-Erk, p-CREB and p-S6 less in CR-Rel than in CCR samples. To predict the response to therapy, multivariate classifiers were better than individual nodes at discriminating between CR-Rel and CCR groups (adjusted AUC*>0.8). Additional analyses that evaluate independence and ability to combine clinical or molecular predictors (e.g., cytogenetics, FLT3 ITD) with SCNP data will be presented. Conclusion: The training study data show the value of performing quantitative SCNP under modulated conditions as the basis for developing highly predictive tests for response to induction chemotherapy in pediatric patients with newly diagnosed AML. Independent validation studies will follow. Disclosures: Lacayo: Nodality Inc.: Honoraria. Cohen:Nodality Inc.: Employment, Equity Ownership. Westfall:Nodality Inc.: Employment, Equity Ownership. Lackey:Nodality Inc.: Employment, Equity Ownership. Xin:Nodality Inc.: Employment, Equity Ownership. Gayko:Nodality Inc.: Employment, Equity Ownership. Putta:Nodality Inc.: Employment, Equity Ownership. Cesano:Nodality Inc.: Employment, Equity Ownership.

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Nilotinib Shows Safety and Efficacy in Older Patients (≥ 65 years) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase Comparable with That in Younger Patients with Chronic Myeloid Leukemia in Chronic Phase: Results From ENESTnd,

Blood ◽

10.1182/blood.v118.21.3768.3768 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3768-3768 ◽

Cited By ~ 5

Author(s):

Richard A. Larson ◽

Udomsak Bunworasate ◽

Anna G. Turkina ◽

Stuart L. Goldberg ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 3768 Background: Data from the phase 3, randomized multicenter ENESTnd trial have demonstrated the superiority of nilotinib over imatinib after 24 months (mo) of follow-up, with significantly higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR), and significantly lower rates of progression to accelerated phase/blast crisis (AP/BC). The current subanalysis evaluated the efficacy and safety of nilotinib 300 mg twice daily (Nil300) and nilotinib 400 mg twice daily (Nil400) in older (≥ 65 years [yrs] at study entry) patients (pts) with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) with a minimum follow-up of 24 mo. Methods: In ENESTnd, 846 pts stratified by Sokal risk score were randomized 1:1:1 to Nil300 (n = 282), Nil400 (n = 281), or imatinib 400 mg once daily (n = 283). Pts with impaired cardiac function or ECOG performance status > 2 were excluded. Rates of CCyR and MMR by 24 mo, progression to AP/BC on treatment, and safety were evaluated according to age group (< 65 vs ≥ 65 yrs) in the 2 nilotinib arms. Safety data are reported for any pt who received ≥ 1 dose of nilotinib (n = 279, Nil300; n = 277, Nil400). Results: 36 pts (13%) and 28 pts (10%) were ≥ 65 yrs old in the Nil300 and Nil400 arms, respectively. Of the pts aged ≥ 65 yrs, 51/64 (80%) had an ECOG performance status of 0 at baseline and 60/64 (94%) had intermediate or high Sokal risk scores. Of the older pts, 8 (22%) on Nil300 and 6 (21%) on Nil400 had type 2 diabetes at baseline. CCyR rates by 24 mo were 83% and 68% among older pts treated with Nil300 and Nil400, respectively, and 87% for pts aged < 65 yrs in each nilotinib arm. By 24 mo, MMR was achieved by 72% and 61% of older pts on Nil300 and Nil400, respectively; in pts aged < 65 yrs, the respective rates were 71% and 67%. All 5 pts who progressed to AP/BC on treatment (2 on Nil300 and 3 on Nil400) were aged < 65 yrs. The frequency of grade 3/4 hematologic adverse events (AEs) was low in older pts; no pts had grade 3/4 neutropenia and only 1 older pt reported grade 3/4 thrombocytopenia in each nilotinib arm (Table). Transient, asymptomatic lipase elevations were reported in 11% and 16% of older pts treated with Nil300 and Nil400, and 7% of younger pts in each arm. Hyperglycemia occurred in 23% and 16% of older pts on Nil300 and Nil400, respectively, and 4% of younger pts in each arm; regardless of age, no pt discontinued study due to hyperglycemia. Among the 12 older pts with grade 3/4 hyperglycemia (8 on Nil300; 4 on Nil400), 9 pts had type 2 diabetes at baseline. There were no QTcF increases of > 60 msec from baseline in older pts and 3 in nilotinib-treated pts < 65 yrs old (1 on Nil300; 2 on Nil400). QTcF prolongation of > 500 msec did not occur in any pt treated with nilotinib on study. Periodic echocardiograms were done, and there were no decreases of > 15% in left ventricular ejection fraction from baseline in any pt treated with nilotinib on study. There were 4 cases of ischemic heart disease reported in older pts (1/35 [3%] on Nil300; 3/25 [12%] on Nil400) and 7 cases in pts < 65 yrs of age (4/244 [2%] on Nil300; 3/252 [1%] on Nil400). No sudden deaths occurred on study. Discontinuation occurred in approximately 25% of older and younger pts with Nil300, of which, 6% and 9%, respectively, were due to AEs/lab abnormalities. Discontinuation from study with Nil400 was 46% in older pts and 19% in younger pts; of which, 36% and 10% were due to AEs/lab abnormalities. Conclusions: Older pts treated with nilotinib demonstrated high rates of cytogenetic and molecular responses and low rates of progression. Nilotinib was generally well tolerated by older pts. In older pts, Nil300 had numerically higher rates of CCyR and MMR and was generally better tolerated (as evidenced by fewer AEs and discontinuations) vs Nil400. These data support the use of Nil300 in older pts with newly diagnosed CML-CP. Disclosures: Larson: Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Bunworasate:Novartis Pharmaceutical: Research Funding. Turkina:Novartis: Consultancy, Honoraria; BMS: Honoraria. Goldberg:Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Dorlhiac-Llacer:Bristol Myers Squibb: Research Funding; Novartis: Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding. Saglio:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hochhaus:Ariad: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Yu:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Clark:Bristol Myers Squibb: Honoraria, Research Funding; Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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CPX-351 ((Cytarabine:Daunorubicin) Liposome Injection, (Vyxeos)) Does Not Prolong Qtcf Intervals, Requires No Dose Adjustment for Impaired Renal Function and Induces High Rates of Complete Remission in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2510.2510 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2510-2510 ◽

Cited By ~ 6

Author(s):

Tara L. Lin ◽

Laura F. Newell ◽

Robert K. Stuart ◽

Laura C. Michaelis ◽

Stephen E. Rubenstein ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Dose Adjustment ◽

Cardiac Repolarization ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar ratio. It is highly effective in patients with high-risk acute myeloid leukemia (AML). This study evaluated the impact of CPX-351 (100 units/m2) on cardiac repolarization. Methods: This open-label, Phase II, pharmacokinetic (PK) and pharmacodynamic (PD) study entered AML and acute lymphocytic leukemia (ALL) patients with good risk hepatic function (Child-Pugh scores <7), and normal cardiac function (LVEF≥50%, QTcF<470 ms). Cardiac repolarization changes were assessed using conventional ECG and Holter monitor recordings. PK was assessed during the first 21 days for total cytarabine, daunorubicin, Ara-U and daunorubicinol. The relationship between CPX-351 PK, QTcF, and renal function using the equation to calculate the estimated glomerular filtration rate (eGFR) was evaluated. Results: Twenty-six patients entered the study and 21 were evaluable for QT interval change from baseline. Evidence that CPX-351 prolongs the QTcF interval was not observed. The largest absolute and mean change from time-matched baseline was 12.56 and 8.03 ms, respectively (Day 1, hour 4). Mean QTcF change on Day 5 was unchanged from baseline. QTcF intervals >480 ms were never observed and no consistent QTcF intervals >450 ms were noted. Absolute QTcF increases between 30 and 60 ms were present in 4 of 25 patients and no changes >60 ms were observed. CPX-351 plasma concentration vs. time curves for day 1 and 5 exhibited a volume of distribution approximately equal to the plasma volume with prolonged single-exponential elimination half-lives for cytarabine and daunorubicin of ≥24 hours. The PK of CPX-351 was independent of renal function. Patients with moderately impaired (eGFR=30-59 mL/min/1.73m2) renal function exhibited similar drug exposure as those with mild and normal renal function. Table 1. Impact of renal function impairment on Day 5 CPX-351 PK parameters (mean, %CV): Analyte Renal Function Cmax (ng/mL) AUClast (ng*hr/mL) AUCinf (ng*hr/mL) T1/2 (hr) Cytarabine Normal (n=3) Mean 59333 2893146 2902641 42.5 %CV 28.7 68.8 69 34.1 Mild (n=7) Mean 58071 3599512 3606695 41.0 %CV 31.9 52.4 52.4 21.8 Moderate (n=3) Mean 57333 3149303 3156738 38.0 %CV 46.6 50.7 50.6 21.9 Daunorubicin Normal (n=3) Mean 25967 754646 870861 24.9 %CV 23.1 63 65.3 56.0 Mild (n=7) Mean 28686 865034 1021420 30.5 %CV 43.9 43.5 43.6 25.3 Moderate (n=3) Mean 21933 671542 814732 35.4 %CV 50.9 35.9 33.5 31.2 Table 2 summarizes response and transplant outcomes. One of two ALL patients achieved CR and was transplanted. Among AML patients there were 7 CR and 2 CRi of which three went on to transplant. An additional four patients became morphologically leukemia free (MLF) and were transplanted before full documentation of CR was achieved. A large majority of patients given first-line treatment with CPX-351 responded or became suitable for transplant (10/13, 77%). Table 2. 206 Study Efficacy Diagnosis n ResponseCR/CRi Transplanted in CR/CRi Induced MLF and Transplanted No Response ALL-Relapsed 2 1/0 1/0 0 1 AML-First Line de novo 8 5/0 0 1 2 AML-First Line sAML 5 1/2 1/1 1 1 AML-Salvage 11 1/0 1/0 2 8 Conclusions: Clinically relevant prolongation of QTcF is not a feature of CPX-351 treatment. CPX-351 exposure was independent of renal function, indicating no need for dose adjustment when renal function is impaired. The high rate of complete remission and referral for transplant corroborate the high level of efficacy observed in earlier studies with CPX-351. Disclosures Stuart: Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Pentikis:Celator Pharmaceuticals: Consultancy. Alvarez:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Mayer:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Burden of Hospitalizations Due to Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disorder (EBV+PTLD) in Patients Who Failed First Line Rituximab or Rituximab Plus Chemotherapy Following Solid Organ Transplant (Post-SOT): A Retrospective Chart Review Study of German PTLD Registry

Blood ◽

10.1182/blood-2019-124583 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 65-65

Author(s):

Heiner Zimmermann ◽

Hairong Xu ◽

Arie Barlev ◽

Yang Zhang ◽

Dhanalakshmi Thirumalai ◽

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Background: Post-transplant lymphoproliferative disorder (PTLD) is a rare and often aggressive disease in the setting of immunosuppression following solid organ transplant (post-SOT). About 50% of cases are associated with Epstein-Barr virus (EBV) infection of B cells, either due to reactivation of the virus after transplantation, or from primary EBV infection. Data remain very limited with respect to overall clinical and economic burden among EBV+PTLD patients (pts), particularly in the setting of pts who fail first line therapy. This retrospective chart review aimed to quantify the burden of hospitalization due to EBV+PTLD in post-SOT pts who failed first-line therapy in the real-world setting in Germany. Study Design and Methods: The German PTLD registry database was screened for pts with EBV+PTLD post-SOT who were refractory (failed to achieve complete [CR] or partial remission [PR]) to rituximab or rituximab plus chemotherapy (CT) or relapsed at any point after such therapy between 2000 to 2015. Pts with primary CNS PTLD were excluded. Pts without any outpatient visit or hospitalization record were excluded from the analysis (n of pts=1). Hospitalization data were reviewed by an experienced physician and adjudicated as PTLD relevant; details on diagnoses and procedures performed during hospitalization were collected from the first diagnosis of PTLD to the earliest of the following: death, loss to follow up or end of study period (Sep 1st, 2018). We estimated the mean number of hospitalizations, average length of inpatient stay per admission and the percentages of time spent in the hospital out of the total time following PTLD index date or treatment failure index date. The PTLD index date was defined as the first date of EBV+PTLD diagnosis; and the treatment failure index date was defined as the earliest date of pts who became refractory or relapsed to first-line therapy of rituximab or rituximab plus CT. Results: A total of 35 EBV+PTLD pts were analyzed. All had failed first line rituximab monotherapy. Median follow up time was 24.8 months from the PTLD index date. Median age at PTLD diagnosis was 47 years (range 18-75). Of these, 6 (17.1%) were polymorphic, 21 (60%) were diffuse large B cell lymphoma, 3 (8.6%) were Burkitt lymphoma, and 5 (14.3%) were other B-cell lymphoma. Among the 35 pts, 23 (65.7%) died: 12 from PTLD, 6 treatment-related, 1 from organ failure, and 4 from other causes. The vast majority of pts (29 out of 35) received CHOP-based CT following rituximab failure (2 other CT, 4 did not receive CT). All pts (100%) had at least one inpatient hospitalization after PTLD diagnosis and 16 (45.7%) pts had at least one ICU admission following PTLD index date. The mean number of PTLD hospitalizations following PTLD index date was 4 (SD 3.2, range 1-12) and the mean average length of stay per hospitalization was 23.8 days (SD 22.6, range 2-94). The mean proportion of time spent in the hospital out of total time at risk from PTLD index date was 20.5% (SD 27.6, range 0.1-100) with an average of 9.5% of time spent in the ICU setting during hospitalization stay (SD 22, range 0-99.5). The mean number of PTLD hospitalizations (n of pts=19) following first course CT failure index date was 2.1 (SD 1.9, range 0-7) and the mean average length of stay per hospitalization was 14.8 days (SD 8.6, range 6-31.6). The mean proportion of time spent in the hospital out of total time at risk from CT failure index date was 41.8% (SD 39.6, range 0-100) with an average of 26% time spent in the ICU setting (SD 39, range 0-100). Conclusions: This is the first study to quantify the hospitalization burden directly related to EBV+PTLD post-SOT in Germany. The results show that hospitalization burden in EBV+PTLD post-SOT pts failing first line rituximab monotherapy is substantial accounting for approximately 20% of patient's time after initial diagnosis of PTLD with around 10% spent in the ICU setting. This hospitalization burden is even higher and accounts for over 40% of time in pts after additional treatment failure to first CT with 26% spent in the ICU setting. Disclosures Zimmermann: Roche: Research Funding; Janssen: Other: Travel, accomodations expenses; Atara Biotherapeutics: Other: Travel, accomodations expenses, Research Funding; Celgene: Other: Travel, accomodations expenses. Xu:Atara Biotherapeutics: Employment, Equity Ownership. Barlev:Atara Biotherapeutics: Employment, Equity Ownership. Zhang:Atara Biotherapeutics: Employment, Equity Ownership. Thirumalai:Atara Biotherapeutics: Employment. Watson:Atara Biotherapeutics: Employment, Equity Ownership. Trappe:Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Congress related travel support; Roche: Consultancy, Honoraria, Other: Congress related travel support, Research Funding; AbbVie: Consultancy, Other: Congress related travel support; Celgene: Other: Congress related travel support.

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